KR102637759B1 - Aryl sulfonamide compounds as carbonic anhydrase inhibitors and their therapeutic uses - Google Patents

Abstract

Disclosed herein are compounds having the following structure that are useful as inhibitors of carbonic anhydrase IX (CAIX) and XII, and are particularly useful in reducing or eliminating metastasis.

Formula (I)

Description

Aryl sulfonamide compounds as carbonic anhydrase inhibitors and their therapeutic uses

technology field

The present invention relates generally to inhibitors of carbonic anhydrase IX (CAIX) and It relates to the use of said compounds to treat and/or prevent various human diseases, including diseases related to CAIX and CAXII in the elimination of.

Explanation of related fields

Hypoxia is a biologically and clinically relevant feature of solid tumors, and its presence has important implications for tumor phenotype, cancer progression, and metastasis, and is associated with poor prognosis in many types of solid tumors (Chaudary and Hill, Breast Dis. 2006-2007, 26:55-64; Milani and Harris, Eur. J. Cancer, 2008, 44(18) :2766-2773). Hypoxia has also been associated with tumor resistance to conventional treatment with radiotherapy and chemotherapy. It is known that a hypoxic environment promotes epithelial to mesenchymal transition (EMT) of cancer cells, causing an increased tendency to metastasize. It is also a niche environment for cancer stem cells (CSCs), a subset of cancer cells with tumor-initiating properties, including the ability to self-renew and resistance to current anti-cancer therapies. environment) (Scheel and Weinberg, Semin. Cancer Biol., 2012, 22(5-6) :396-403). Importantly, the inability to effectively eradicate these aggressive treatment-resistant tumor cells leads to recurrence and distant metastases, truly fatal aspects of cancer.

The ability of cancer cells to adapt to innately hostile hypoxia conditions provides a selective advantage over normal cells and supports their expansion and dissemination (Sedlakova et al ., Front. Physiol., 2014, 4 :400 ). Adaptation of cancer cells to hypoxia results in increased production of acidic metabolites, including lactic acid, protons, and carbon dioxide (CO ₂ ) (Parks et al ., J. Cell Physiol., 2011, 226(2) :299-308 ) induction of the glycolytic switch (Sedlakova et al ., Front. Physiol., 2014, 4:400; Gatenby and Gillies, Nat. Rev. Cancer., 2008, 8(1) :56-61; Neri and Supuran, Nat. Rev. Drug Discov., 2011, 10(10) :767-77) of the HIF-1α signaling cascade (Lendhal et al. ., Nat. Rev. Genet., 2009, 10(12) :821-32). To avoid long-term intracellular acidosis, a condition that rapidly affects cellular functions essential for cell survival (Gatenby and Gillies, Nat. Rev. Cancer., 2004, 4(11) :891-899; Neri and Supuran, Nat. Rev. Drug Discov., 2011, 10(10) :767-77) Tumor cells activate a network of proteins and buffer systems that function to maintain pH homeostasis (Gatenby and Gillies, Nat. Rev Cancer., 2004, 4(11) :891-899; Neri and Supuran, Nat. Rev. Drug Discov., 2011, 10(10) :767-77; Fang et al., Semin. Cancer Biol., 2008 , 18(5) :330-7; Gatenby and Gillies, Nat. Rev. Cancer., 2008, 8(1) :56-61). Membrane-bound, exofacial carbonic anhydrases, especially tumor-specific CAIX and CAXII, are key components of this pH regulation system (Neri and Supuran, Nat. Rev. Drug Discov., 2011, 10(10) :767 -77; Supuran, Nat. Rev. Drug Discov., 2008, 7(2) :168-81; McDonald et al ., Oncotarget., 2012, 3(1) :84-97).

CAIX is a cell surface, HIF-1α-inducible metalloenzyme that promotes the reversible hydration of CO ₂ into bicarbonate (HCO ₃ ^- ) and protons (H ⁺ ) (Gatenby and Gillies, Nat. Rev. Cancer. , 2008, 8(1) :56-61). In hypoxic tumors, CAIX allows maintaining a pH favorable for cancer cell survival and growth and simultaneously participates in extracellular acidification, enabling tumor cell migration, invasion, and metastasis (Swietach et al., J. Biol Chem., 2009, 284(30) :20299-310; Supuran, Nat. Rev. Drug Discov., 2008, 7(2) :168-81). Additionally, inhibiting CAIX or inhibiting its activity results in the elimination of cancer stem cells and inhibition of EMT. Therefore, inhibiting CAIX activity disrupts pH regulation, reducing cancer cell (particularly cancer stem cell) growth, attenuating invasion, and ultimately inhibiting tumor growth and metastasis (Supuran, Nat. Rev. Drug Discov ., 2008, 7(2) :168-81; Lou et al., Cancer Res., 2011, 71(9) :3364-76). CAIX expression is very limited in human normal tissues, but overexpression in solid tumors is associated with poor prognosis in many cancers, including lung, colon, breast, cervix, bladder, pancreas, ovary, brain, head and neck, and oral cavity. It is done. Additionally, clinical studies have revealed a correlation between CAIX expression and metastatic disease (Lou et al ., Cancer Res., 2011, 71(9) :3364-76; Loncaster et al ., Cancer Res., 2001, 61 (17) :6394-9; Kim et al ., J. Cancer Res. Clin. Oncol., 2006, 132(5) :302-8; De Schutter et al ., BMC Cancer, 2005, 5:42; Liao et al ., Gynecol. Oncol., 2010, 116(3) :452-8.; Garcia et al ., Hum. Pathol., 2007, 38(6) :830-41).

CAIX is an attractive target for anticancer therapy for several reasons. It is selectively expressed on the extracellular surface of tumor cells and shows very limited expression in normal tissues (Supuran, Nat. Rev. Drug Discov., 2008, 7(2) :168-81). It is a functional regulator of processes key to tumor growth and metastasis, including pH regulation, survival, and adhesion/migration. Additionally, genetic silencing of CAIX in an in vivo preclinical tumor model demonstrated the requirement of CAIX for the growth of hypoxic tumors and their metastasis (Chiche et al ., Cancer Res., 2009, 69 (1) :358-368; Lou et al ., Cancer Res., 2011, 71(9) :3364-76; McIntyre et al ., Clin. Cancer Res., 2012, 18(11) :3100-11) .

CAXII, similar to CAIX, is a membrane-bound, external carbonic anhydrase that catalyzes the reversible hydration of carbon dioxide (Gatenby and Gillies, Nat. Rev. Cancer., 2004, 4(11) :891-899; Wykoff et al. , Am. J. Pathol., 2001, 158(3) :1011-9). Similar to CAIX, its expression is restricted in normal tissues, but it is expressed in many types of human cancer, including pancreatic, colon, oral, brain, lung, ovarian, breast, and T-cell lymphomas, and also regulates pH and cancer. May be involved in cell survival (Watson et al., Br. J. Cancer, 2003, 88(7) :1065-70; Wykoff et al., Am. J. Pathol., 2001, 158(3) :1011 -9; Gondi et al., Cancer Res., 2013, 73(21) :6494-503; Ilie et al., Lung Cancer, 2013, 82(1) :16-23; Gatenby & Gillies, Nat. Rev. Cancer., 2004, 4(11) :891-899). It is noteworthy that co-expression of CAIX and CAXII is evident in some types of cancer, suggesting that some degree of redundancy may exist between CAIX and CAXII in these cases (McIntyre et al., Clin Cancer Res., 2012, 18(11) :3100-11). In cancer types where both isoforms are expressed or where inhibition of CAIX results in partial compensation by CAXII, simultaneous selective inhibition of both targets may be necessary.

summary

The present invention provides aryl sulfonamide derivatives that can inhibit the activity of CAIX and CAXII. Methods of using the derivatives to inhibit the activity of CAIX and CAXII and pharmaceutical compositions comprising the derivatives are also disclosed.

One embodiment provides a compound of formula (I), a stereoisomer, enantiomer or tautomer thereof, an isotopically enriched derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. :

here,

R ¹ is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, or alkoxy;

R ² , R ³ , R ⁴ , and R ⁵ are the same or different and are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, amino, halo, or haloalkyl;

R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different and are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, amino, halo, or haloalkyl;

L is a direct bond or (C(R ¹⁰ ) ₂ ) _p ;

n = 1, 2 or 3;

p = 1 to 4;

Each R ¹⁰ is the same or different and is independently hydrogen or alkyl;

However, the compound of formula (I) is 4-[3-[cis-4-(aminomethyl)-4-(3-chlorophenyl)cyclohexyl]-2-oxo-1-imidazolidinyl]-benzenesulfone It's not amide.

A further embodiment provides compounds of formula (I) wherein n is 1 and R ² , R ³ , R ⁴ , R ⁵ are each hydrogen, which compounds have the structure of formula (Ia):

Here, R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , L and p are as defined above.

Another embodiment presents compounds of formula (II):

Here, R ¹ , R ² , R ³ , R 4 , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^{10 ,} L, n and p are as defined above, except that Formula (II) The compound is not 4-[3-[cis-4-(aminomethyl)-3-(3-chlorophenyl)cyclohexyl]-2-oxo-1-imidazolidinyl]benzenesulfonamide.

Another embodiment provides a pharmaceutical composition comprising a compound of any one of formula (I), (Ia), or (II) and a pharmaceutically acceptable excipient.

A further embodiment is a solid tumor expressing CAIX comprising administering to a subject in need of treatment a pharmaceutically effective amount of a compound of formula (I), (Ia) or (II) or a pharmaceutical composition comprising the same. suggests a method of treating .

In more specific embodiments, the cancer includes, but is not limited to, astrocytoma/glioblastoma, bladder cancer, breast cancer, colon carcinoma, esophageal adenocarcinoma, gastrointestinal stromal tumor, stomach cancer, head and neck cancer, hepatocellular carcinoma, lung cancer, melanoma, ovarian cancer, and pancreatic ductal adenocarcinoma. , may be renal cell carcinoma, thyroid cancer, or endometrial cancer.

DETAILED DESCRIPTION OF THE INVENTION

Justice

Particular chemical groups named herein are preceded by an abbreviated designation indicating the total number of carbon atoms to be found in the indicated chemical group. For example, C ₇ -C ₁₂ alkyl refers to an alkyl group having a total of 7 to 12 carbon atoms as defined below, and C ₄ -C ₁₂ cycloalkylalkyl refers to an alkyl group having a total of 4 to 12 carbon atoms as defined below. It represents a cycloalkylalkyl group having a carbon atom. The total number of carbons in the abbreviated designation does not include carbons that may be present in substituents of the disclosed groups.

Accordingly, as used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings indicated:

“Amino” refers to the -NH ₂ radical.

“Cyano” refers to the -CN radical.

“Nitro” refers to the -NO ₂ radical.

“Oxo” refers to the =O substituent.

“thioxo” refers to the =S substituent.

“Alkyl”, when unsubstituted, consists only of carbon and hydrogen atoms, contains no unsaturations, and has 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms or 1 to 6 carbon atoms; refers to a straight or branched hydrocarbon chain radical that is attached to the rest of the molecule by a single bond, for example methyl, ethyl, n -propyl, 1-methylethyl ( iso -propyl), n -butyl, n -pentyl , 1,1-dimethylethyl ( t -butyl), etc. Unless stated otherwise specifically herein, an alkyl group may be optionally substituted by one of the following groups: alkenyl, amino, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl. , heteroaryl, -OR ¹⁴ , -OC(O)R ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)OR ¹⁶ , -N(R ¹⁴ )C(O)R ¹⁶ , -N(R ¹⁴ )(S(O) _t R ¹⁶ ) (where t is 1 to 2), -S(O) _t OR ¹⁶ (where t is 1 to 2), -S(O) _t R ¹⁶ (where t is 0 to 2), and -S(O) _t N (R ¹⁴ ) ₂ , where t is 1 to 2, where each R ¹⁴ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; Each R ¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, where each of the above substituents is substituted unless otherwise indicated. It doesn't work. Accordingly, “alkyl” includes unsubstituted and substituted alkyl.

“Alkenyl” means that, when unsubstituted, it consists only of carbon and hydrogen atoms, contains at least one double bond, has 2 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and is formed by a single bond. Refers to a straight or branched hydrocarbon chain radical attached to the rest of the molecule, such as ethenyl, prop-1-enyl, but-1-enyl, and pentyl. (pent)-1-enyl, penta (penta)-1,4-dienyl, etc. Unless stated otherwise specifically herein, an alkenyl group may be optionally substituted by one of the following groups: alkyl, amino, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR ¹⁴ , -OC(O)R ¹⁴ , -N(R ¹⁴ )2, -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)OR ¹⁶ , -N(R ¹⁴ )C(O)R ¹⁶ , -N( R ¹⁴ )(S(O) _t R ¹⁶ ) (where t is 1 to 2), -S(O) _t OR ¹⁶ (where t is 1 to 2), -S(O) _t R ¹⁶ (where t is 0 to 2), and -S(O) _t N(R ¹⁴ ) ₂ (where t is 1 to 2), where each R ¹⁴ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; Each R ¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, where each of the above substituents is unsubstituted. Accordingly, “alkenyl” includes unsubstituted and substituted alkenyl.

“Alkylene” or “alkylene chain” connects the remainder of the molecule to a radical, consists only of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. It refers to a straight or branched divalent hydrocarbon chain having carbon, such as methylene, ethylene, propylene, n -butylene, etc. The alkylene chain can be attached to the rest of the molecule and to the radical group via one carbon in the chain or any two carbons in the chain.

“Alkoxy” refers to a radical of the formula -OR _a , where R _a is an alkyl radical as defined above. The alkyl portion of the alkoxy radical may be optionally substituted as defined above for alkyl radicals. In particular, the alkyl portion of alkoxy may be further substituted with amino, halo, haloalkyl, haloalkenyl, cyano, hydroxy, nitro, or alkoxy.

“Aryl”, when unsubstituted, refers to an aromatic monocyclic or polycyclic hydrocarbon ring system consisting solely of hydrogen and carbon and containing 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms, wherein The ring system may be partially saturated. Aryl groups may include, but are not limited to, groups such as fluorenyl, phenyl, and naphthyl. Unless specifically stated otherwise herein, the term "aryl" or the prefix "ar-" (e.g., in "aralkyl") means 1 selected from the group consisting of: It is meant to include an aryl radical optionally substituted by one or more substituents: alkyl, alkenyl, amino, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, Heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R ¹⁵ OR ¹⁴ , R ¹⁵ -OC(O)-R ¹⁴ , -R ¹⁵ -N(R ¹⁴ ) ₂ , -R ¹⁵ -C( O)R ¹⁴ , -R ¹⁵ -C(O)OR ¹⁴ , -R ¹⁵ -C(O)N(R ¹⁴ ) ₂ , -R ¹⁵ -N(R ¹⁴ )C(O)OR ¹⁶ , -R ¹⁵ -N(R ¹⁴ )C(O)R ¹⁶ , -R ¹⁵ -N(R ¹⁴ )(S(O) _t R ¹⁶ ) (where t is 1 to 2), -R ¹⁵ -S(O) _t OR ¹⁶ (where t is 1 to 2), -R ¹⁵ -S(O) _t R ¹⁶ (where t is 0 to 2), -R ¹⁵ -S(O) _t N(R ¹⁴ ) ₂ (where t is 1 to 2), where each R ¹⁴ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R ¹⁵ is independently a direct bond or a straight or branched alkylene or alkenylene chain; Each R ¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, where each of the above substituents is unsubstituted. Accordingly, “aryl” includes unsubstituted and substituted aryl.

“Aralkyl” refers to a radical of the formula -R _a R _b where R _a is an alkyl radical as defined above and R _b is one or more aryl radicals as defined above, for example benzyl, di phenylmethyl, etc. The aryl portion of the aralkyl radical may be optionally substituted as described above for the aryl group. The alkyl portion of the aralkyl radical may be optionally substituted as defined above for the alkyl group.

“Aralkenyl” refers to a radical of the formula -R _c R _b , where R _c is an alkenyl radical as defined above and R _b is one or more aryl radicals as defined above, which are as disclosed above. Together, they may be arbitrarily substituted. The aryl portion of the aralkenyl radical may be optionally substituted as described above for the aryl group. The alkenyl portion of the aralkenyl radical may be optionally substituted as defined above for the alkenyl group.

"Cycloalkyl", when unsubstituted, consists only of carbon and hydrogen atoms, has 3 to 15 carbon atoms, preferably has 3 to 12 carbon atoms, is saturated or unsaturated and is attached to the remainder of the molecule by single bonds. Refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon radical attached to a moiety, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, etc. Unless specifically stated otherwise herein, the term “cycloalkyl” is meant to include cycloalkyl radicals optionally substituted by one or more substituents selected from the group consisting of: alkyl, alkenyl, amino, Halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R ¹⁵ -OR ¹⁴ , - R ¹⁵ -OC(O)R ¹⁴ , -R ¹⁵ -N(R ¹⁴ ) ₂ , -R ¹⁵ C(O)R ¹⁴ , -R ¹⁵ C(O)OR ¹⁴ , -R ¹⁵ -C(O)N (R ¹⁴ ) ₂ , -R ¹⁵ -N(R ¹⁴ )C(O)OR ¹⁶ , -R ¹⁵ -N(R 14 )C(O)R ¹⁶ , -R ^{15 -N} (R ¹⁴ )(S( O) _t R ¹⁶ ) (where t is 1 to 2), -R ¹⁵ -S(O) _t OR ¹⁶ (where t is 1 to 2), -R ¹⁵ -S(O) _t R ¹⁶ (where t is 0 to 2), and -R ¹⁵ -S(O) _t N(R ¹⁴ ) ₂ (where t is 1 to 2), where each R ¹⁴ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R ¹⁵ is independently a direct bond or a straight or branched alkylene or alkenylene chain; Each R ¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, where each of the above substituents is unsubstituted. Accordingly, “cycloalkyl” includes unsubstituted and substituted cycloalkyl.

“Cycloalkylalkyl” refers to a radical of the formula -R _a R _d , where R _a is an alkyl radical as defined above and R _d is a cycloalkyl radical as defined above. The cycloalkyl portion of the cycloalkyl radical may be optionally substituted as defined above for the cycloalkyl radical. The alkyl portion of the cycloalkyl radical may be optionally substituted as defined above for the alkyl radical.

“Halo” refers to bromo, chloro, fluoro, or iodo.

“Haloalkyl” refers to an alkyl radical as defined above which is substituted by one or more halo radicals as defined above. One or more carbons of the alkyl radical may be substituted by one or more halo radicals. Examples of haloalkyls include, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo. -2-fluoro-propyl, 1-bromomethyl-2-bromoethyl, etc. The alkyl portion of the haloalkyl radical may be optionally substituted as defined above for the alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring containing as ring atoms at least one carbon atom and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Refers to radicals. For the purposes of the present invention, a heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; The nitrogen atom may be optionally quaternized; Heterocyclyl radicals may be partially or fully saturated. Examples of the heterocyclyl radical include dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydryl. Indolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl , pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thio. Including, but not limited to, morpholinyl. Unless otherwise specifically stated herein, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above, optionally substituted by one or more substituents selected from the group consisting of: Alkyl, alkenyl, amino, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, Heteroarylalkyl, -R ¹⁵ -OR ¹⁴ , -R ¹⁵ -OC(O)-R ¹⁴ , -R ¹⁵ -N(R ¹⁴ ) ₂ , -R ¹⁵ -C(O)R ¹⁴ , -R ¹⁵ -C (O)OR ¹⁴ , -R ¹⁵ -C(O)N(R ¹⁴ ) ₂ , -R ¹⁵ -N(R ¹⁴ )C(O)OR ¹⁶ , -R ¹⁵ -N(R ¹⁴ )C(O) R ¹⁶ , -R ¹⁵ -N(R ¹⁴ )(S(O) _t R ¹⁶ ) (where t is 1 to 2), -R ¹⁵ -S(O) _t OR ¹⁶ (where t is 1 to 2) 2), -R ¹⁵ -S(O) _t R ¹⁶ (where t is 0 to 2), and -R ¹⁵ -S(O) _t N(R ¹⁴ ) ₂ (where t is 1 to 2) is), where each R ¹⁴ is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R ¹⁵ is independently a direct bond or a straight or branched alkylene or alkenylene chain; Each R ¹⁶ is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, wherein each of the above substituents is unsubstituted. . Heterocyclyl as defined herein may be monovalent or divalent. When heterocyclyl is a substituent on another moiety, the heterocyclyl is monovalent, meaning that the heterocyclyl is connected to the other moiety by a single ring atom. An example of a monovalent heterocyclyl can be found in the radical of heterocyclylalkyl, where the heterocyclyl group is a substituent for an alkyl group. When heterocyclyl is a linker moiety, heterocyclyl is a divalent radical. Accordingly, “heterocyclyl” includes unsubstituted and substituted heterocyclyl.

“Heterocyclylalkyl” refers to a radical of the formula -R _a R _e , where R _a is an alkyl radical as defined above, R _e is a heterocyclyl radical as defined above, and heterocyclyl is In the case of nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. The alkyl portion of the heterocyclylalkyl radical may be optionally substituted as defined above for the alkyl group. The heterocyclyl portion of the heterocyclylalkyl radical may be optionally substituted as defined above for the heterocyclyl group.

“Heteroaryl” refers to a 5- to 18-membered aromatic ring radical containing as ring atoms at least 1 carbon atom and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For the purposes of the present invention, heteroaryl radicals may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused or bridged ring systems; The nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; The nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxo. benzodioxolyl, benzodioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzoyl [4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, Isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, Phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, furinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyradiginyl, quinazolinyl, quinoxalinyl, quinolinyl , quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless otherwise specifically stated herein, the term “heteroaryl” is meant to include heteroaryl radicals as defined above, optionally substituted by one or more substituents selected from the group consisting of: alkyl, Alkenyl, amino, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl Alkyl, -R ¹⁵ -OR ¹⁴ , -R ¹⁵ -OC(O)-R ¹⁴ , -R ¹⁵ -N(R ¹⁴ ) ₂ , -R ¹⁵ -C(O)R ¹⁴ , -R ¹⁵ -C(O )OR ¹⁴ , -R ¹⁵ -C(O)N(R ¹⁴ ) ₂ , -R ¹⁵ -N(R ¹⁴ )C(O)OR ¹⁶ , -R ¹⁵ -N(R ¹⁴ )C(O)R ¹⁶ , -R ¹⁵ -N(R ¹⁴ )(S(O) _t R ¹⁶ ) (where t is 1 to 2), -R ¹⁵ -S(O) _t OR ¹⁶ (where t is 1 to 2) ), -R ¹⁵ -S(O) _t R ¹⁶ (where t is 0 to 2), and -R ¹⁵ -S(O) _t N(R ¹⁴ ) ₂ (where t is 1 to 2) , where each R ¹⁴ is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R ¹⁵ is independently a direct bond or a straight or branched alkylene or alkenylene chain; Each R ¹⁶ is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, wherein each of the above substituents is unsubstituted. . Heteroaryl as defined herein may be monovalent or divalent. When heteroaryl is a substituent on another moiety, the heteroaryl is monovalent, meaning that the heteroaryl is connected to the other moiety by a single ring atom. Examples of monovalent heteroaryls can be found in the radicals of heteroarylalkyl, where the alkyl group is replaced by a heteroaryl group. When heteroaryl is a linker, heteroaryl is a divalent radical. Accordingly, “heteroaryl” includes unsubstituted and substituted heteroaryl.

“Heteroarylalkyl” refers to a radical of the formula -R _a R _f , where R _a is an alkyl radical as defined above and R _f is a heteroaryl radical as defined above. The heteroaryl portion of the heteroarylalkyl radical may be optionally substituted as defined above for the heteroaryl group. The alkyl portion of the heteroarylalkyl radical may be optionally substituted as defined above for the alkyl group.

“Prodrug” refers to a compound that can be converted to a biologically active compound of any one of formula (I), (Ia) or (II) under physiological conditions or by solvolysis. Accordingly, the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of any one compound of formula (I), (Ia) or (II); The latter is also referred to as the “parent compound”. Prodrugs are inactive when administered to a subject in need of treatment, but are converted in vivo to the active compound, i.e. the parent compound. Prodrugs are typically rapidly converted in vivo to produce the parent compound, for example by hydrolysis in the blood. Prodrug compounds usually offer the advantages of solubility, tissue compatibility or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs (1985), pp. 79, 2124, Elsevier, Amsterdam).

The term “prodrug” is also meant to include any covalently linked carrier that releases the active compound of the invention in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present invention can be prepared by modifying functional groups present in any one compound of formula (I), (Ia) or (II), wherein the modifications can be made by routine manipulation or It is decomposed into the parent compound in vivo . The prodrug comprises a compound of any one of formula (I), (Ia) or (II), wherein the hydroxy group, amino group or mercapto group is cleaved upon administration of the prodrug to a mammalian subject, forming a free hydroxy group, respectively; It is bonded to any group to restore a free amino group or a free mercapto group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate, and phosphate derivatives of the alcohol or amine function in any one compound of formula (I), (Ia) or (II). no.

“Stable compound” and “stable structure” refer to a compound that is sufficiently potent to survive isolation from a reaction mixture to useful purity and formulation into an effective therapeutic agent.

“Mammal” or “mammalian subject” or “subject” includes humans and livestock, such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits, etc.

“Optional” or “optionally” means that an instance of a subsequently disclosed circumstance may or may not occur, and that the disclosure includes instances in which the instance or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may be substituted or unsubstituted and that the disclosure includes both substituted aryl radicals and aryl radicals without substitution.

“Pharmaceutically acceptable carrier, diluent or excipient” means, but is not limited to, any adjuvant, carrier, excipient, or glidant approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock. , sweetening agents, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.

“Pharmaceutically acceptable acid addition salts” are those that retain the biological effectiveness and properties of the biologically or otherwise desirable free base, and include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and acetic acid. , 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidebenzoic acid, camphor acid, camphor-10-sulfonic acid, capric acid, caproic acid, carboxylic acid Prilylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid , galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycol Acids, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucilic acid, naphthalene-1,5-disulfonic acid, naphthalene -2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4 -Aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p -toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc. refer to salts formed from organic acids.

“Pharmaceutically acceptable base addition salt” refers to a salt that retains the biological effectiveness and properties of the biologically or otherwise desirable free acid. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethyl. Amine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, pro Caine, hydrabamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperi. It includes, but is not limited to, dine, N -ethylpiperidine, polyamine resin, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Crystallization usually produces solvates of the compounds of the invention. As used herein, the term “solvate” refers to an aggregate comprising one or more molecules of a compound of the invention together with one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention may exist in hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as corresponding solvated forms. While the compounds of the invention are true solvates, in other cases, the compounds of the invention may only retain adventitious water or be a mixture of water and some adventitious solvent.

“Pharmaceutical composition” refers to a formulation of a compound of the invention and a biologically active compound in a vehicle generally accepted in the art for delivery to a mammal, e.g., a human. The medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.

“Therapeutically effective amount” refers to an amount of a compound of the invention, as defined below, sufficient to treat a disease or condition in a mammal, preferably a human, when administered to a mammal, preferably a human. The amount of a compound of the invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and severity thereof of the mammal being treated, and the age, but can be determined routinely by one of ordinary skill in the art and having regard to the present invention.

As used herein, “treating” or “treatment” encompasses treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or disorder of interest;

(i) preventing the development of a disease or condition in a mammal, especially when the mammal is predisposed to have the condition but has not yet been diagnosed as having the condition;

(ii) inhibiting the disease or condition, i.e. preventing its development; or

(iii) alleviating the disease or condition, i.e. causing regression of the disease or condition;

Includes.

As used herein, the terms “disease” and “condition” may be used interchangeably or may differ in that a particular disease or condition may not have a known pathogen (the etiology is not yet known), so that However, it is only recognized as an undesirable condition or syndrome in which a certain set of symptoms has been identified by clinicians.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, and thus may have a molecular weight relative to an amino acid in terms of absolute stereochemistry as ( R )- or (S)-, or (D) - or (L). Enantiomers, diastereomers, and other stereoisomeric forms may occur. The present invention is intended to include all such possible isomers as well as their racemic and optionally pure forms. Optionally the active (+) and (-), ( R )- and (S)-, or (D)- and (L)- isomers are prepared using chiral synthons or chiral reagents, or by conventional techniques. For example, it can be dissolved using HPLC using a chiral column. When compounds disclosed herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

“Stereoisomers” refer to compounds consisting of identical atoms joined by identical bonds, but having different three-dimensional structures, which cannot be interchanged. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposeable mirror images of the other.

“Tautomerism” refers to the proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of the above compounds.

An “isotopically enriched derivative” is one in which one or more atoms are replaced by an atom with the same atomic number but a different atomic mass or mass number than that commonly found in nature. Refers to a compound. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ² H and ³ H, isotopes of carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, isotopes of chlorine, such as ³⁸ CI, Isotopes of fluorine, such as ¹⁸ F, isotopes of iodine, such as ¹²³ I and ¹²⁵ I, isotopes of nitrogen, such as ¹³ N and ¹⁵ N, isotopes of oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O, isotopes of phosphorus. elements such as ³¹ P, ³² P and ³³ P, and isotopes of sulfur such as ³⁵ S. Substitution with a heavier isotope such as deuterium, i.e. ² H, may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. , and therefore may be desirable in some situations. Isotopically-enriched compounds of the present invention are generally prepared by conventional techniques known to those skilled in the art or by processes similar to those disclosed in the appended Examples and Preparation sections using appropriate isotopically-enriched reagents in place of the non-enriched reagents previously used. It can be manufactured by.

The chemical naming protocol and structure diagrams used herein utilize and rely on chemical naming features as used by Chemdraw version 12.0.2.1076 (available from Cambridgesoft Corp., Cambridge, Mass.).

For example, as disclosed above in the Summary of the Invention, R ¹ is 3,4-difluorophenyl, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R A compound of formula (I) wherein ⁹ is each hydrogen, L is a direct bond and n is 1, i.e. the following structure:

The compound is named herein as 4-(3-(3,4-difluorophenyl)-2-oxoimidazolidin-1-yl)benzene-sulfonamide.

Embodiments of the Invention

Embodiment

One embodiment provides a compound of formula (I), a stereoisomer, enantiomer or tautomer thereof, an isotopically enriched derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof:

here,

R ¹ is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, or alkoxy;

R ² , R ³ , R ⁴ , and R ⁵ are the same or different and are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, amino, halo, or haloalkyl;

R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different and are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, amino, halo, or haloalkyl;

L is a direct bond or (C(R ¹⁰ ) ₂ ) _p ;

n = 1, 2 or 3;

p = 1 to 4;

Each R ¹⁰ is the same or different and is independently hydrogen or alkyl;

However, the compound of formula (I) is 4-[3-[cis-4-(aminomethyl)-4-(3-chlorophenyl)cyclohexyl]-2-oxo-1-imidazolidinyl]-benzenesulfone It's not amide.

A further embodiment includes compounds of formula (I) wherein n is 1 and R ² , R ³ , R ⁴ , R ⁵ are each hydrogen, said compounds being represented by the structure (Ia) below, stereoisomers, mirror images thereof: Isomers or tautomers, isotopically enriched derivatives thereof, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, or prodrugs thereof are provided:

here,

R ¹ is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, or alkoxy;

R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different and are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, amino, halo, or haloalkyl;

L is a direct bond or (C(R ¹⁰ ) ₂ ) _p ;

p = 1 to 4;

Each R ¹⁰ is the same or different and is independently hydrogen or alkyl;

However, the compound of formula (I) is 4-[3-[cis-4-(aminomethyl)-4-(3-chlorophenyl)cyclohexyl]-2-oxo-1-imidazolidinyl]-benzenesulfone It's not amide.

In various embodiments, R ¹ is aryl, including substituted aryl, and L is a direct bond or methylene (-CH ₂ -).

In a more specific embodiment, R ¹ is substituted aryl (e.g., phenyl) substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy, heterocyclyl, haloalkyl, cyano, and acetyl. .

In a more specific embodiment, the compound of formula (I) or (Ia) is:

4-(3-(4-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(2,4-difluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(2-oxo-3-( p -tolyl)imidazolidin-1-yl)benzenesulfonamide;

4-(3-(2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(3-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(3,5-dimethylphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(2-oxo-3-(3,4,5-trimethoxyphenyl)imidazolidin-1-yl)benzenesulfonamide;

4-(3-(2-fluoro-4-morpholinophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(4-bromo-2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(4-chloro-2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)benzenesulfonamide;

4-(3-(4-chloro-3-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(2-fluoro-4-methoxyphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(4-(2-methoxyethoxy)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(2-isopropylphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(3,5-difluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(3-chloro-4-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(3,4-difluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(2-chloro-5-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(4-butoxy-2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(4-butoxyphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-(4-cyanophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide; or

4-(3-(4-acetylphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide.

In other embodiments, R ¹ is cycloalkyl, including substituted cycloalkyl, and L is a direct bond or methylene (-CH ₂ -).

In a more specific embodiment, the compound of formula (I) or (Ia) is:

4-(3-cyclopentyl-2-oxoimidazolidin-1-yl)benzenesulfonamide;

4-(3-cyclohexyl-2-oxoimidazolidin-1-yl)benzenesulfonamide; or

4-(3-(Cyclopropylmethyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide.

In other embodiments, R ¹ is heteroaryl, including substituted heteroaryl, and L is a direct bond or methylene (-CH ₂ -).

In a more specific embodiment, the compound of formula (I) or (Ia) is 4-(3-(5-fluoropyridin-2-yl)-2-oxoimidazolidin-1-yl)benzenesulfonamide. .

Another embodiment provides a compound of formula (II), a stereoisomer, enantiomer or tautomer thereof, an isotopically enriched derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof:

here,

R ¹ is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, or alkoxy;

R ² , R ³ , R ⁴ , and R ⁵ are the same or different and are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, amino, halo, or haloalkyl;

R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different and are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, amino, halo, or haloalkyl;

L is a direct bond or (C(R ¹⁰ ) ₂ ) _p ;

n = 1, 2 or 3;

p = 1 to 4;

Each R ¹⁰ is the same or different and is independently hydrogen or alkyl;

However, the compound of formula (II) is 4-[3-[cis-4-(aminomethyl)-3-(3-chlorophenyl)cyclohexyl]-2-oxo-1-imidazolidinyl]-benzenesulfone It's not amide.

Another embodiment provides a pharmaceutical composition comprising a compound of formula (I), (Ia) or (II) and a pharmaceutically acceptable excipient.

Another embodiment is a method of inhibiting tumor growth, invasion and/or tumor metastasis in a mammal, comprising comprising a pharmaceutical composition having any one compound of Formula (I), (Ia) or (II), comprising: A method including the step of administering is presented.

Another embodiment is a method of reducing breast cancer cell number or mass in a mammal, comprising administering to said mammal a pharmaceutical composition having any one compound of formula (I), (Ia) or (II). Presents a method that includes .

Another embodiment is a method for removing cancer stem cells from a population of mammalian cancer stem cells, comprising contacting the population of mammalian cancer stem cells with a compound of any one of Formula (I), (Ia), or (II). suggests a way to do it.

Another embodiment provides a method of inducing cell death in hypoxic cancer cells, comprising contacting the hypoxic cancer cells with a compound of any one of Formula (I), (Ia), or (II).

Tumors or cancer cells that can be treated include tumors or cancer cells of breast, lung, pancreas, kidney, prostate, cervix, colon, or glioblastoma, according to various embodiments. Any cancer or tumor or cell population treated herein may express CAIX or CAXII above normal levels for non-cancerous pseudo-derived tissue.

In particular, treating a mammal with cancer or a tumor using the pharmaceutical composition of the present invention includes reducing or eliminating metastases.

In more specific embodiments, the cancer being treated includes, but is not limited to, astrocytoma/glioblastoma, bladder cancer, breast cancer, colon carcinoma, esophageal adenocarcinoma, gastrointestinal stromal tumor, stomach cancer, head and neck cancer, hepatocellular carcinoma, lung cancer, melanoma, ovarian cancer, pancreas. Includes ductal adenocarcinoma, renal cell carcinoma, thyroid cancer, or endometrial cancer.

In further embodiments, the treatment methods disclosed herein may include administering (simultaneously or sequentially) an additional chemotherapy agent or other anti-cancer agent.

Use and Testing of Compounds of the Invention

The present invention relates to compounds, pharmaceutical compositions and methods using said compounds and diseases and conditions mediated by the activity of CAIX or CAXII individually or by any combination thereof, preferably angiogenesis and/or cell proliferation and It relates to a pharmaceutical composition for the treatment and/or prevention of diseases and conditions characterized by movement, especially diseases and conditions related to cancer, etc., by administering an effective amount of the compound of the present invention.

The compounds of the present invention modulate, preferably inhibit, the activity of human CAIX or CAXII individually or in any combination thereof.

The general value of the compounds of the present invention in controlling, especially inhibiting, the activity of CAIX or CAXII individually or in any combination thereof was determined using the assay disclosed in Example 29 below. can be decided.

The compounds of the invention are inhibitors of CAIX or CAXII, individually or any combination thereof, and are the result of the abnormal activity of CAIX or CAXII, individually or any combination thereof, or of the activity of CAIX or CAXII, individually or any combination thereof. It is useful for treating diseases and disorders in humans and other organisms, including all of the above human diseases and disorders that can be ameliorated by modulation.

As defined herein, a disease or condition mediated by abnormal activity of CAIX or CAXII, individually or in any combination thereof, means increased activity of CAIX or CAXII, individually or in any combination thereof, and/or abnormal activity of CAIX or CAXII individually or in any combination thereof. It is defined as any disease or condition in which inhibition of the activity of or any combination thereof can be demonstrated to cause symptomatic improvement in the subject being treated. As defined herein, a disease or condition mediated by CAIX or CAXII individually or in any combination thereof includes, but is not limited to, cancer or a disease or condition related thereto. For the purposes of this invention, diseases and conditions ameliorated by modulation of CAIX or CAXII individually or in any combination thereof include breast, kidney, endometrium, ovarian, thyroid, and non-small cell lung carcinoma. solid tumors, including but not limited to carcinoma), melanoma, prostate carcinoma, sarcoma, gastric cancer, and uveal melanoma; Vascular disease/injury, including but not limited to endometriosis, restenosis, atherosclerosis and thrombosis, psoriasis; Visual impairment due to macular degeneration; diabetic retinopathy and retinopathy of prematurity; Kidney disease, including but not limited to glomerulonephritis, diabetic kidney disease and renal transplant rejection, rheumatoid arthritis; Includes, but is not limited to, osteoarthritis, osteoporosis, and cataracts.

In addition to the above, the compounds of the present invention are useful in treating diseases and conditions affected by the following biological processes: invasion, migration, metastasis, or drug resistance as seen in cancer; Stem cell biology as seen in cancer; Infiltration, migration, adhesion, or angiogenesis as seen in endometriosis; vascular remodeling, as seen in cardiovascular disease, hypertension, or vascular injury; bone homeostasis, as seen in osteoporosis or osteoarthritis; Viral infections, for example, as seen in Ebola virus infection; or differentiation as seen in obesity.

The following animal models provide guidance to those skilled in the art in testing compounds of the invention for use in treating indicated diseases or conditions.

The compounds of the present invention include HT-29, PDAC, MDA-MB-231, SK-OV-3, OVCAR-8, DU145, H1299, ACHN, A498 and Caki-1, respectively, or the step of administering a pharmaceutically effective amount. their use in the treatment of solid tumors by testing the compounds in xenografts in a SCID mouse model using human cancer cell lines expressing, but not limited to, CAIX or CAXII or co-expressing any combination thereof. It can be used or examined for:

The compounds of the invention can be used or tested for their use in the treatment of endometriosis, respectively, by administering a pharmaceutically effective amount to a subject in need of treatment or by using a syngenic mouse model of endometriosis. (See Somigliana, E. et al., "Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis", Hum. Reprod. 1999, 14(12), 2944-2950). The compounds can also be tested for their use in the treatment of endometriosis by using a rat model of endometriosis (Lebovic, D.I. et al., “Peroxisome proliferator-activated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis", Fertil. Steril., 2004, 82 Suppl 3, 1008-1013).

Typically, a therapeutic agent that successfully inhibits the activity of CAIX or CAXII, individually or in any combination thereof, will meet some or all of the following criteria. Oral solubility should be greater than 20%, animal model efficacy should be less than about 20 mg/Kg, 2 mg/Kg, 1 mg/Kg, or 0.5 mg/Kg, and target human dose should be 10 to 250 mg/70 Kg, Capacities outside this range may be acceptable. (“mg/Kg” means milligrams of compound per kilogram of body mass of the subject to which the compound is administered). The required administration schedule should preferably be no more than about once or twice per day or at mealtimes. The therapeutic index (or ratio of toxic dose to therapeutic dose) should be greater than 10. IC ₅₀ (“Inhibitory Concentration - 50%”) is a measure of the amount of compound required to achieve 50% inhibition of kinase activity over a specific period of time in a kinase activity assay. Any procedure that measures the kinase activity of CAIX or CAXII, preferably human CAIX or CAXII, can be used to assay the activity of compounds useful in the methods of the invention in inhibiting said CAIX or CAXII activity. The compounds of the invention are preferably present at less than 10 μM, less than 5 μM, less than 2.5 μM, less than 1 μM, less than 750 nM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM in a 15 to 60 minute recombinant human assay. exhibits an IC ₅₀ of less than, and most preferably less than 20 nM. The compounds of the present invention may exhibit reversible or irreversible inhibition, and preferably do not inhibit other carbonic anhydrase enzymes.

The activity of compounds of the invention as CAIX or CAXII inhibitors can be tested using recombinant human CAIX or CAXII proteins and using the stopped-flow method, procedures known to those skilled in the art or as described in Example 29. did. When tested in this assay, the compounds of the invention exhibit an inhibitory activity of greater than 50% at a concentration of 10 μM of the test compound, preferably greater than 60% of an inhibition activity of the test compound at a concentration of 10 μM, more preferably an inhibitory activity of greater than 60% at a concentration of 10 μM of the test compound. an inhibition activity of greater than 70% at a concentration of 10 μM, and even more preferably an inhibition activity of greater than 80% at a concentration of 10 μM of the test compound, and most preferably an inhibition activity of greater than 90% at a concentration of 10 μM of the test compound. Therefore, it was demonstrated that the compounds of the present invention are potential inhibitors of the activities of CAIX and CAXII.

These results provide the basis for structure-activity relationship (SAR) analysis between the test compounds and the inhibitory activity of CAIX or CAXII. Certain groups tend to present more potent inhibitory compounds. SAR analysis is one of the tools of skill in the art that can be used to identify preferred embodiments of compounds of the invention for use as therapeutic agents. Other methods for testing the compounds disclosed herein are also readily available to those skilled in the art. Therefore, determination of the ability of a compound to inhibit CAIX or CAXII activity can also be accomplished in vivo. In one embodiment, this is accomplished by administering the chemical agent to an animal model that has received a specific tumor xenograft and subsequently detecting changes in tumor growth rate in the animal to identify therapeutic agents useful for the treatment of the tumor. do. In this embodiment, the animal can be a human, such as a human patient suffering from a disease and in need of treatment for the disease.

In certain embodiments of the in vivo process, the change in CAIX or CAXII activity in the animal is a decrease in activity, and preferably the CAIX or CAXII inhibitor does not substantially inhibit the biological activity of other carbonic anhydrases. No.

The compounds of the present invention can be used in combination with other therapeutic agents. Examples of alkylating agents that can be carried out in combination include fluorouracil (5-FU) alone or in further combination with leukovorin; Other pyrimidine analogs such as UFT, capecitabine, gemcitabine and cytarabine, alkyl sulfonates such as busulfan (used in the treatment of chronic granulocytic leukemia), improsulfan and piposulfan; Aziridines such as benzodepa, carboquone, meturedepa and uredepa; ethyleneimine and methylmelamine, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and triethylolmelamine; and nitrogen mustards, such as chlorambucil (used in the treatment of chronic lymphocytic leukemia, primary macroglobulinemia, and non-Hodgkin's lymphoma), cyclophosphamide (Hodgkin's (used to treat multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms tumor, and rhabdomyosarcoma), estramustine, ifosfamide, and novembrichin ), prednimustine, and uracil mustard (used in the treatment of primary thrombocytosis, non-Hodgkin's lymphoma, Hodgkin's disease, and ovarian cancer); and triazines, such as dacarbazine (used in the treatment of soft tissue sarcoma).

Examples of antimetabolite chemotherapy agents that can be performed in combination include folic acid analogs, such as methotrexate (acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes, breast cancer, head and neck cancer and osteogenic sarcoma) used in the treatment of) and pteropterin; and purine analogs such as mercaptopurine and thioguanine, which are used in the treatment of acute granulocytic, acute lymphoid, and chronic granulocytic leukemia. Examples of natural product-based chemotherapy agents that can be carried out in combination include vinca alkaloids, such as vinblastine (used in the treatment of breast and testicular cancer), vincristine and vindesine; epipodophyllotoxins, such as etoposide and teniposide, both of which are useful in the treatment of testicular cancer and Kaposi's sarcoma; Antibiotic chemotherapy agents, such as daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat stomach, cervical, colon, breast, bladder, and pancreatic cancer), dactinomycin, and temozolomide ( temozolomide), plicamycin, bleomycin (used to treat cancers of the skin, esophagus, and genitourinary tract); and enzymatic chemotherapy agents such as L-asparaginase.

Examples of other signal transduction inhibitors that can be performed in combination include gefitinib, erlotinib, sorafenib, herceptin, imatinib, dasatinib, sunitinib, nilotinib, lapatinib, and pazopanib. , vandetanib, vemurafenib, crizotinib, ruxolitinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, ponatinib, Dabra Includes, but is not limited to, penib, trametinib, and afatinib.

Other agents that may be used in combination with the compounds of the present invention include, but are not limited to, Vioxx, Celebrex (celecoxib), valdecoxib, paracoxib, and rofecoxib. COX-II inhibitor; Including, but not limited to, matrix metalloproteinase inhibitors such as AG-3340, RO 32-3555, and RS 13-0830.

Pharmaceutical composition and administration of the present invention

The present invention also relates to pharmaceutical compositions containing any one compound of formula (I), (Ia) or (II) disclosed herein. In one embodiment, the present invention, when administered to an animal, preferably a mammal, most preferably a human patient, modulates the activity of CAIX or CAXII, individually or in any combination thereof, or modulates angiogenesis and/or cell proliferation. and a composition comprising any one compound of formula (I), (Ia) or (II) in a pharmaceutically acceptable carrier in an amount effective for treating diseases related to migration, and especially cancer. In an embodiment of the composition, the patient has a solid tumor that expresses CAIX prior to administration of the compound of the invention, and the compound of the invention is present in an amount effective to modulate or inhibit over-expression of CAIX.

The pharmaceutical compositions useful herein also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which itself will not induce the production of antibodies harmful to the subject receiving the composition and can be administered without undue toxicity. Includes any drug that can be used. Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol, and ethanol. A detailed discussion of pharmaceutically acceptable carriers, diluents, and other excipients is presented in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J. current edition).

Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, etc.), dosage form, suitable pharmaceutical excipients, and other issues related to the delivery of a compound to a subject in need of treatment.

In alternative uses of the invention, the compounds of the invention may be used in vitro or in vivo as exemplary agents for comparative purposes to discover other compounds that are also useful in the treatment or protection from the various diseases disclosed herein. Can be used in research.

Administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, in pure form or as appropriate pharmaceutical compositions can be accomplished through any of the accepted modes of pharmaceutical administration that provide similar utility. Pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present invention with appropriate pharmaceutically acceptable carriers, diluents or excipients, and may be in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, powders, granules. , ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering the pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalational, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical composition of the present invention is formulated so that the active ingredients contained in the composition are bioavailable upon administration to a patient. The composition to be administered to a subject or patient may take the form of one or more dosage units, for example a tablet may be a single dosage unit and a container of the compound of the invention in aerosol form may hold a plurality of dosage units. can do. The actual methods of preparing the dosage forms are known to, or will be apparent to, those skilled in the art; See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will in any case contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of the disease or condition of interest in accordance with the teachings of the invention.

The pharmaceutical composition of the present invention may exist in solid or liquid form. In one aspect, the carrier(s) are particulate so that the composition may be in, for example, tablet or powder form. The carrier(s) may be liquid, such that the composition is, for example, an oral oil, an injectable solution or an aerosol useful, for example, for inhalation administration.

When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, where forms contemplated herein as solid or liquid include semi-solid, semi-liquid, suspension and gel forms.

As a solid composition for oral administration, the pharmaceutical composition may be formulated in the form of powder, granules, compressed tablets, pills, capsules, gum, wafers, etc. The solid composition will typically contain one or more inert diluents or edible carriers. Additionally, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; Excipients such as starch, lactose or dextrin, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch, etc.; Lubricants such as magnesium stearate or Sterotex; Glidants such as colloidal silicon dioxide; Sweeteners such as sucrose or saccharin; Flavoring agents such as peppermint, methyl salicylate or orange flavoring; and colorants.

When the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, it may contain, in addition to substances of the above types, a liquid carrier such as polyethylene glycol or oil.

Pharmaceutical compositions may be in liquid form, for example as elixirs, syrups, solutions, emulsions or suspensions. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred compositions contain, in addition to the compounds of the invention, one or more sweeteners, preservatives, dyes/colorants and flavor enhancers. Compositions intended to be administered by injection may include one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers, and isotonic agents.

Liquid pharmaceutical compositions of the present invention in the form of solutions, suspensions, etc. may contain one or more of the following adjuvants: sterile diluents such as water for injection, saline, preferably physiological saline, Ringer's solution solution), isotonic sodium chloride, fixed oils, such as synthetic mono- or diglycerides, polyethylene glycol, glycerin, propylene glycol or other solvents that can serve as solvent or suspending medium; Antibacterial agents such as benzyl alcohol or methyl paraben; Antioxidants such as ascorbic acid or sodium bisulfite; Chelating agents such as ethylenediaminetetraacetic acid; Buffers such as acetate, citrate or phosphate and tonicity agents such as sodium chloride or dextrose. Parenteral preparations may be administered in ampoules, disposable syringes, or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. The injectable pharmaceutical composition is preferably sterile. Liquid pharmaceutical compositions of the invention intended for parenteral or oral administration should contain a significant amount of the compound of the invention so that a suitable dosage is obtained. Typically this amount is at least 0.01% of the compound of the invention in the composition. When intended for oral administration, this amount can vary from 0.1 to about 70% of the weight of the composition. Preferred oral pharmaceutical compositions contain from about 4% to about 75% of the compounds of the invention. Preferred pharmaceutical compositions and formulations according to the invention are prepared so that the parenteral dosage unit contains 0.01 to 10% by weight of the compound of the invention prior to dilution.

The pharmaceutical composition of the present invention may be intended for topical administration, in which case the carrier may suitably include a solution, emulsion, ointment or gel base. The base may include, for example, one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in pharmaceutical compositions for topical administration. When intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of a compound of the invention from about 0.1 to about 10% w/v (weight per unit volume). The pharmaceutical composition of the present invention may be intended for rectal administration, for example in the form of a suppository that dissolves in the rectum and releases the drug. Compositions for rectal administration may contain an oleaginous base as a suitable non-irritating excipient. The bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol. Pharmaceutical compositions of the present invention may contain various substances that modify the physical form of the solid or liquid dosage unit. For example, the composition may include a material that forms a coating shell around the active ingredient. The materials forming the coating shell are typically inert and may be selected from, for example, sugar, shellac, and other enteric coatings. Alternatively, the active ingredient may be embedded within a gelatin capsule.

The pharmaceutical composition of the present invention in solid or liquid form may contain an agent that binds to the compound of the present invention and aids delivery of the compound. Suitable agents that can act in this capacity include monoclonal or polyclonal antibodies, proteins or liposomes. The pharmaceutical composition of the present invention may be formulated in dosage units that can be administered as an aerosol. The term aerosol is used to refer to a variety of systems ranging from those of a colloidal nature to systems comprised of pressurized packages. Delivery may be by liquefied or compressed gas or by a suitable pump system dispensing the active ingredient. Aerosols of the compounds of the invention may be delivered in single-phase, two-phase, or three-phase systems to deliver the active ingredient(s). Aerosol delivery includes the necessary containers, activators, valves, subcontainers, etc., which together can form a kit. One skilled in the art can determine the preferred aerosol without undue experimentation. The pharmaceutical composition of the present invention can be prepared by methods well known in the pharmaceutical industry. For example, pharmaceutical compositions intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water to form a solution. Surfactants may be added to enable the formation of a homogeneous solution or suspension. Surfactants are compounds that interact non-covalently with the compounds of the invention to enable dissolution or homogeneous suspension of the compounds in an aqueous delivery system.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, depending on the activity of the specific compound used; the metabolic stability and length of action of the compound; The patient's age, weight, general health, gender, and diet; Mode and time of administration; excretion rate; Combining medications; The severity of a particular disorder or condition; and the subject receiving treatment. Generally, a therapeutically effective daily dose is from about 0.001 mg/kg (i.e., 0.7 mg) to about 100 mg/kg (i.e., 7.0 gm) (for a 70 kg mammal); Preferably the therapeutically effective dose is from about 0.01 mg/kg (i.e. 7 mg) to about 50 mg/kg (i.e. 3.5 g) (for a 70 kg mammal); More preferably, the therapeutically effective dose is from about 1 mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 g) (for a 70 kg mammal).

A compound of any one of Formula (I), (Ia) or (II), or a pharmaceutically acceptable derivative thereof, may also be administered concurrently with, prior to, or subsequent to the administration of one or more other therapeutic agents. there is. The combination therapy includes administration of a single pharmaceutical dosage form containing a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage form. do. For example, the compounds of the present invention and other active agents may be administered to a patient together in a single oral dosage composition such as a tablet or capsule, or as each agent administered in separate oral dosage formulations. When separate dosage forms are used, the compound of the invention and one or more additional active agents can be administered essentially at the same time, i.e. simultaneously, or at separate staggered times, i.e. sequentially; Combination therapy is understood to include all of these therapies.

Isotopic enrichment of compounds

Isotopic enrichment is the process by which the relative abundance of isotopes of a given element is altered, forming a form of the element in which one particular isotope is enriched and its other isotopes are depleted. Isotopic enrichment of drugs is used for the following applications: reduction or elimination of undesirable metabolites; Increased half-life of the parent drug; Reduce the number of doses needed to achieve the desired effect; Reduce the dosage required to achieve the desired effect; Increased formation of active metabolites, if any are formed; and/or reducing the formation of harmful metabolites in specific tissues and/or creating more effective and/or safer drugs for combination therapy, whether the combination therapy is intentional or not.

Substitution of an atom for one of the isotopes will usually cause a change in the rate of the chemical reaction. This phenomenon is known as the Kinetic Isotope Effect. For example, if a CH bond is broken during the rate-determining step (i.e., the step with the highest transition state energy) in a chemical reaction, substitution of a deuterium for the hydrogen will cause a decrease in the reaction rate, and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (Foster et. al., Adv . Drug Res ., 1985, 14, 1-36; Kushner et. al., Can. J. Physiol . Pharmacol ., 1999, 77, 79-88).

Improvement of the metabolism, pharmacokinetics, pharmacodynamics, and toxicity profile of drugs by isotopic enrichment, such as digestion, has been demonstrated by the following examples: Lijinsky et. al., J. Nat. Cancer Inst ., 1982, 69, 1127-1133; Gately et. al., J. Nucl . Med ., 1986, 27, 388-394; Gordon et. al., Drug Metab . Dispos ., 1987, 15, 589-594; Mangold et. al., Mutation Res ., 1994, 308, 33-42; Zello et. al., Metabolism , 1994, 43, 487-491; Wade D., Chem . Biol . Interact ., 1999, 117, 191-217.

Preparation of Compounds of the Invention

In the following description, it is understood that combinations of substituents and/or variables of the depicted formulas are permitted only if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in the processes disclosed below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. The functional groups include hydroxy, amino, mercapto, and carboxylic acids. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t -butyldimethylsilyl, t -butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. . Suitable protecting groups for amino, amidino, and guanidino include t -butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" where R" is alkyl, aryl or arylalkyl, p -methoxybenzyl, trityl, etc. Suitable protecting groups for carboxylic acids include alkyl, aryl or arylalkyl esters.

Protecting groups may be added or removed according to standard techniques, as are well known to those skilled in the art and disclosed herein.

The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. The protecting group may also be a polymer resin such as Wang resin or 2-chlorotrityl-chloride resin.

It is also known to those skilled in the art that the protected derivatives of the compounds of the present invention do not have the above-mentioned pharmaceutical activity, but can be metabolized in the body after administration to a mammal to form pharmaceutically active compounds of the present invention. will be recognized Accordingly, the derivative may be described as a “prodrug”. All prodrugs of the compounds of the invention are included within the scope of the invention.

The following reaction scheme illustrates the method for preparing the compounds of the present invention. It is understood that one skilled in the art will be able to prepare these compounds by similar methods or methods known to those skilled in the art. Typically, starting ingredients are from Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA. USA), or synthesized according to materials known to those skilled in the art (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or according to the present invention. Can be prepared as disclosed.

In general, compounds of formula (I) wherein L is a direct bond, R ⁴ and R ⁵ are hydrogen, and n is 1 can be synthesized according to the general procedure as disclosed in Scheme 1. X represents Cl or Br.

Scheme 1

Starting materials for the above schemes are commercially available or can be prepared by methods known to those skilled in the art or by methods disclosed herein. In general, the compounds of the present invention can be prepared by the above reaction scheme as follows.

The starting aryl sulfonamide (101) reacts with haloacetyl halide (102) to produce compound (103). Amine (104) is treated with compound (103) to produce compound (105), which is reduced by a reducing agent such as, but not limited to, borane to produce compound (106). This diamine compound is cyclized by treatment with triphosgene to obtain an imidazolidinone compound of formula (I) of the present invention in which L is a direct bond, R ⁴ and R ⁵ are hydrogen, and n is 1. do.

Alternatively, compounds of formula (I) of the invention wherein L is a direct bond, R ⁴ and R ⁵ are hydrogen, and n is 1 can be synthesized according to conventional procedures as shown in Scheme 2.

Scheme 2

Starting materials for the above schemes are commercially available or can be prepared by methods known to those skilled in the art or by methods disclosed herein. In general, the compounds of the present invention can be prepared by the above reaction scheme as follows.

Compound (103) is reduced using a reducing agent such as, but not limited to, borane to produce compound (201), which is then treated with amine (104) to produce diamine compound (202). This diamine compound is cyclized by treatment with triphosgene to obtain the imidazolidinone compound of formula (1) of the present invention in which L is a direct bond, R ⁴ and R ⁵ are hydrogen, and n is 1.

More details on the syntheses of compounds of formula (I), (Ia) or (II) are provided herein. Unless otherwise specified, all reagents and reaction conditions used in the synthesis are known to those skilled in the art and are available from conventional commercial sources.

Manufacturing example

Manufacturing Example 1

Preparation of 2-bromo- N -(4-sulfamoylphenyl)acetamide

Sulfanilamide (8.61 g, 50.0 mmol) was suspended in acetone (20 mL) and the suspension was cooled to 0 °C in an ice bath. Bromoacetyl bromide (4.14 mL, 47.5 mmol) was added dropwise. After a white solid appeared, the reaction mixture was heated to 55° C. for 10 minutes with stirring. The mixture was cooled to ambient temperature, ice water was added, stirred briefly and filtered. The collected solid was washed with more ice water and then suspended in ethanol (100 mL). The suspension was stirred at ambient temperature for 20 minutes and filtered. The white solid was collected and dried under vacuum to give the title compound in 42% yield (5.85 g). ^1H NMR (300 MHz, DMSO- d6 ) δ 10.72 (s, 1H), 10.01 (s, 1H), _7.90-7.80 (m, 4H), 7.80-7.73 (m, 4H), 7.28 (br s, 2H), 4.09 (s, 2H), 4.04 (s, 2H).

Production example 2

Preparation of 2-chloro- N -(4-sulfamoylphenyl)acetamide

Sulfanilamide (10.0 g, 58.1 mmol) was suspended in acetone (30 mL) and chloroacetylchloride (4.49 mL, 55.3 mmol) was added dropwise at ambient temperature. The reaction mixture was stirred at 95° C. for 1 hour and then cooled to ambient temperature. Ice water was added and the resulting mixture was stirred for a moment and filtered. The collected solid was washed with ice water and recrystallized from ethanol. The solid was collected by filtration and dried in vacuo to give the title compound as a white solid (8.84 g) and the filtrate was concentrated to give more product (3.42 g). The total yield was 89%. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.61 (s, 1H), 7.81-7.71 (m, 4H), 7.26 (br s, 2H), 4.29 (s, 2H).

Production example 3

Preparation of 2-((3-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Mix 2-chloro- N -(4-sulfamoylphenyl)acetamide (108 mg, 0.434 mmol), 3-fluoroaniline (0.25 mL, 2.57 mmol), and potassium iodide (10 mg) in 15 mL of tetrahydrofuran. did. The mixture was stirred at 110° C. overnight, cooled to ambient temperature and concentrated. The residue was purified by column chromatography eluting with dichloromethane:methanol (100:1 to 100:3, then 10:1) to give the title compound as an off-white solid in 60% yield (83.6 mg). did. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.37 (s, 1H), 7.80-7.73 (m, 4H), 7.47-7.41 (m, 1H), 7.23 (br s, 2H), 7.12-7.04 (m, 1H), 6.87 (br s, 1H), 6.61-6.55 (m, 1H), 5.80 (br s, 1 H), 3.95 (d, J = 6.0 Hz, 2H).

Preparation Example 3.1

Preparation of 2-((3,5-dimethylphenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, the title compound was prepared with the modification of using 3,5-dimethylaniline instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide. It was obtained as a white solid in 70% yield. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.24 (s, 1H), 7.80-7.73 (m, 4H), 7.23 (br s, 2H), 6.24 (s, 1H), 6.22 (s, 2H) ), 5.78 (br s, 1H), 3.86 (br s, 2H), 2.13 (s, 6H).

Preparation Example 3.2

Preparation of N -(4-sulfamoylphenyl)-2-((3,4,5-trimethoxyphenyl)amino)acetamide

Following the procedure described in Preparation Example 3, a modification was made to use 3,4,5-trimethoxyaniline instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide. , the title compound was obtained in 38% yield as a brownish solid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.32 (s, 1H), 7.76-7.70 (m, 4H), 7.21 (br s, 2H), 5.91 (s, 2H), 5.79 (t, J = 6.4 Hz, 1H), 3.86 (d, J = 6.4 Hz, 2H), 3.66 (s, 6H), 3.50 (s, 3H).

Preparation Example 3.3

Preparation of 2-(cyclopentylamino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, with the modification of using cyclopentanamine instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide, the title compound is obtained as a white solid. Obtained in 84% yield. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.79-7.71 (m, 4H), 7.22 (br s, 2H), 3.50 (s, 2H), 3.21-3.11 (m, 1H), 1.84-1.34 (m, 8H).

Preparation Example 3.4

Preparation of 2-(cyclohexylamino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, with the modification of using cyclohexanamine instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide, the title compound is obtained as a white solid. Obtained in 71% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.77-7.71 (m, 4H), 7.22 (br s, 2H), 3.47 (s, 2H), 2.58-2.52 (m, 1H), 1.84-1.79 (m, 2H), 1.70-1.62 (m, 2H), 1.58-1.50 (m, 1H), 1.23-1.00 (m, 5H).

Preparation Example 3.5

Preparation of 2-((4-bromo-2-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, a modification was made to use 4-bromo-2-fluoroaniline instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide. , the title compound was obtained in 80% yield as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.32 (s, 1H), 7.77-7.71 (m, 4H), 7.32-7.28 (m, 1H), 7.21 (br s, 2H), 7.15-7.10 (m, 1H), 6.57 (t, J = 8.8 Hz, 1H), 5.97 (br s, 1H), 3.96 (s, 2H).

Preparation Example 3.6

Preparation of 2-((4-chloro-2-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, a modification was made to use 4-chloro-2-fluoroaniline instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide, The title compound was obtained in 80% yield as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.32 (s, 1H), 7.76-7.70 (m, 4H), 7.22-7.18 (m, 3H), 7.03-6.99 (m, 1H), 6.61 ( t, J = 8.8 Hz, 1H), 3.96 (s, 2H).

Preparation Example 3.7

Preparation of N -(4-sulfamoylphenyl)-2-((4-(trifluoromethyl)phenyl)amino)acetamide

A modification was made to use 4-(trifluoromethyl)aniline instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide, according to the procedure described in Preparation Example 3, The title compound was obtained in 47% yield as a white solid.

Preparation Example 3.8

Preparation of 2-((4-fluorobenzyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, the title compound was obtained with the modification of using 4-fluorobenzylamine instead of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide. was obtained as a white solid in quantitative yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.11 (br s, 1H), 7.77-7.71 (m, 4H), 7.51-7.45 (m, 2H), 7.41-7.35 (m, 2H), 7.28 -7.18 (m, 4H), 7.15-7.09 (m, 2H), 4.00 (s, 2H), 3.72 (s, 2H).

Preparation Example 3.9

Preparation of 2-((cyclopropylmethyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, with the modification of using cyclopropylmethanamine instead of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide, the title compound was obtained as a white color. Obtained as a solid in 77% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.79-7.71 (m, 4H), 7.20 (br s, 2H), 3.31 (s, 2H), 2.39 (d, J = 6.8 Hz, 1H), 0.93-0.83 (m, 1H), 0.40-0.35 (m, 2H), 0.10-0.05 (m, 2H).

Preparation Example 3.10

Preparation of 2-((2-isopropylphenyl)amino)- N -(4-sulfamoylphenyl)acetamide

The title compound was prepared according to the procedure described in Preparation Example 3, with the modification of using 2-isopropylaniline instead of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide. It was obtained as a white solid in 63% yield. ^1H NMR (400 MHz, DMSO- d ₆ ): δ 10.32 (s, 1H), 7.77-7.72 (m, 4H), 7.22 (br s, 2H), 7.05 (dd, J = 7.6, 1.6 Hz, 1H ), 7.00-6.94 (m, 1H), 6.62-6.57 (m, 1H), 6.40 (dd, J = 7.6, 1.2 Hz, 1H), 5.38 (br s, 1H), 3.94 (s, 2H), 3.06 -2.98 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H).

Preparation Example 3.11

Preparation of 2-((2-chloro-5-(trifluoromethyl)phenyl)amino)- N -(4-sulfamoylphenyl)acetamide

The procedure described in Preparation Example 3, with the modification of using 2-chloro-5-trifluoromethylaniline in place of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide. Accordingly, the title compound was obtained as a white solid in 30% yield. ^1H NMR (400 MHz, DMSO- d ₆ ): δ 10.45 (s, 1H), 7.77-7.70 (m, 4H), 7.49 (dd, J = 8.0, 0.8 Hz, 1H), 7.22 (br s, 2H) ), 6.93-6.89 (m, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.14 (t, J = 6.0 Hz, 1H), 4.13 (d, J = 6.0 Hz, 2H).

Preparation Example 3.12

Preparation of 2-((2-fluoro-5-(trifluoromethyl)phenyl)amino) -N- (4-sulfamoylphenyl)acetamide

A modification was made to use 2-fluoro-5-trifluoromethylaniline instead of 3-fluoroaniline, which reacts with 2-bromo- N - (4-sulfamoylphenyl) acetamide, as described in Preparation Example 3. Following the procedure, the title compound was obtained in 37% yield as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.38 (s, 1H), 7.76-7.70 (m, 4H), 7.28-7.18 (m, 3H), 6.94-6.88 (m, 2H), 6.28- 6.20 (m, 1H), 4.06 (d, J = 6.0 Hz, 2H).

Preparation Example 3.13

Preparation of 2-((4-(2-methoxyethoxy)phenyl)amino)- N -(4-sulfamoylphenyl)acetamide

The procedure described in Preparation Example 3, with a modification using 4-(2-methoxyethoxy)aniline instead of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide. Accordingly, the title compound was obtained as a brown solid in 41% yield.

Preparation Example 3.14

Preparation of 2-((4-butoxyphenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, the title compound was prepared with the modification of using 4-butoxyaniline instead of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide. Obtained as a white solid in 86% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.21 (s, 1H), 7.75-7.70 (m, 4H), 7.20 (br s, 2H), 6.73-6.68 (m, 2H), 6.56-6.50 (m, 2H), 3.83-3.77 (m, 4H), 1.64-1.56 (m, 2H), 1.42-1.32 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H).

Preparation Example 3.15

N -(4-sulfamoylphenyl)-2-( p -tolylamino)acetamide

Following the procedure described in Preparation Example 3, with the modification of using p-toluidine in place of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide, the title compound was prepared as a white solid. Obtained in 35% yield.

Preparation Example 3.16

Preparation of 2-((2-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, with the modification of using 2-fluoroaniline instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide, the title compound was obtained as a white color. Obtained as a solid in 26% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.34 (s, 1H), 7.85-7.70 (m, 4H), 7.23 (br s, 2H), 7.10-6.90 (m, 2H), 6.67-6.55 (m, 2H), 5.75 (t, J = 6.3 Hz, 1H), 3.97 (d, J = 6.3 Hz, 2H).

Preparation Example 3.17

Preparation of 2-((2,4-difluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, the title compound was prepared with the modification of using 4-difluoroaniline instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide. It was obtained as a white solid in 42% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.34 (s, 1H), 7.85-7.70 (m, 4H), 7.22 (br s, 2H), 7.20-7.05 (m, 1H), 6.60-6.90 (m, 2H), 6.70-6.55 (m, 1H), 5.70 (m, 1H), 3.97 (d, J = 6.3 Hz, 2H).

Preparation Example 3.18

Preparation of 2-((4-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, with the modification of using 4-fluoroaniline instead of 3-fluoroaniline, which reacts with 2-chloro- N -(4-sulfamoylphenyl)acetamide, the title compound was obtained as a white color. Obtained as a solid in 23% yield.

Preparation Example 3.19

Preparation of 2-((3-chloro-4-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, a modification was made to use 3-chloro-4-fluoroaniline instead of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide. , the title compound was obtained in 66% yield as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.33 (s, 1H), 7.77-7.73 (m, 4H), 7.22 (br s, 2H), 7.10 (t, J = 9.2 Hz 1H), 6.70 (dd, J = 6.4, 3.2 Hz, 1H), 6.58-6.50 (m, 1H), 3.90 (s, 2H).

Preparation Example 3.20

Preparation of 2-((3,5-difluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, a modification was made to use 3,5-difluoroaniline instead of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide, The title compound was obtained in 67% yield as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.39 (s, 1H), 7.77-7.70 (m, 4H), 7.27 (br s, 2H), 6.30-6.15 (m, 4H), 3.93 (s) , 2H).

Preparation Example 3.21

Preparation of 2-((3,4-difluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

A modification was made to use 3,4-difluoroaniline instead of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide, according to the procedure described in Preparation Example 3, The title compound was obtained as a brown solid in 96% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.32 (s, 1H), 7.75-7.65 (m, 4H), 7.30-7.05 (m, 3H), 6.65-6.50 (m, 2H), 6.45- 6.30 (m, 1H), 3.90 (s, 2H).

Preparation Example 3.22

Preparation of 2-((2-fluoro-4-methoxyphenyl)amino)- N -(4-sulfamoylphenyl)acetamide

The procedure described in Preparation Example 3 was performed with the modification of using 2-fluoro-4-methoxyaniline instead of 3-fluoroaniline, which reacts with 2-bromo- N - (4-sulfamoylphenyl) acetamide. Accordingly, the title compound was obtained as a brown solid in 94% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.32 (s, 1H), 7.73 (br s, 4H), 7.21 (br s, 2H), 6.77 (dd, J = 10.8, 2.8 Hz, 1H) , 6.57 (td, J = 8.8, 2.8 Hz, 1H), 6.35 (dd, J = 8.8, 3.2 Hz, 1H), 5.18 (br s, 1H), 3.90 (s, 2H), 3.81 (s, 3H) .

Preparation Example 3.23

Preparation of 2-((4-butoxy-2-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

The procedure described in Preparation Example 3 was performed with the modification of using 4-butoxy-2-fluoroaniline instead of 3-fluoroaniline, which reacts with 2-bromo- N - (4-sulfamoylphenyl) acetamide. Accordingly, the title compound was obtained as a white solid in 73% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.36 (s, 1H), 7.77-7.70 (m, 4H), 7.22 (br s, 2H), 6.78-6.72 (m, 1H), 6.58-6.52 (m, 1H), 6.38-6.32 (m, 1H), 5.13 (br s, 1H), 3.98 (t, J = 6.0 Hz, 2H), 3.91 (t, J = 7.5 Hz, 2H), 1.75-1.70 (m, 2H), 1.49-1.43 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H).

Preparation Example 3.24

Preparation of 2-((4-chloro-3-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide

Following the procedure described in Preparation Example 3, a modification was made to use 4-chloro-2-fluoroaniline instead of 3-fluoroaniline, which reacts with 2-bromo- N -(4-sulfamoylphenyl)acetamide. , the title compound was obtained in 80% yield as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.34 (s, 1H), 7.80-7.65 (m, 4H), 7.30-7.10 (m, 3H), 6.54 (dd, J = 12.5, 2.6 Hz, 1H), 6.43 (dd, J = 8.8, 2.6 Hz, 1H), 3.94 (s, 2H).

Production example 4

Preparation of 4-((2-bromoethyl)amino)benzenesulfonamide

2-Bromo- N -(4-sulfamoylphenyl)acetamide (1.82 g, 6.21 mmol) was suspended in tetrahydrofuran (10 mL) and borane dimethyl sulfide complex (2 M in tetrahydrofuran, 7.75 mL, 15.5 mmol) was added slowly at ambient temperature. The mixture was refluxed for 1 hour and then cooled to ambient temperature. Methanol (10 mL) was added at 0°C, and the resulting mixture was stirred at 0°C for 10 minutes. The pH was changed to <2 by bubbling hydrogen chloride (gas). The mixture was then refluxed for 30 minutes and cooled to ambient temperature. The residue was treated with aqueous sodium hydroxide to pH>12, extracted with ethyl acetate (3*80 mL) and dried over MgSO ₄ . After filtration and solvent removal, the residue was treated with dichloromethane and filtered. The collected solid was dried under vacuum to give the title compound as an off-white solid in 67% yield (1.15 g). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.52-7.47 (m, 2H), 6.90 (br s, 2H), 6.67-6.63 (m, 2H), 6.60 (t, J = 6.0 Hz, 1H ), 3.58-3.47 (m, 4H).

Preparation Example 4.1

Preparation of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide

Instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide, which reacts with the borane dimethyl sulfide complex, 2-((3-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide is used. Following the procedure described in Preparation Example 4, with the modifications used, the title compound was obtained in quantitative yield as a brown liquid and used in the next reaction step without further purification.

Preparation Example 4.2

Preparation of 4-((2-((3,5-dimethylphenyl)amino)ethyl)amino)benzenesulfonamide

2-((3,5-dimethylphenyl)amino)- N -(4-sulfamoylphenyl)acetamide instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacts with borane dimethyl sulfide complex Following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 56% yield. ¹ H NMR (300 MHz, DMSO- d ₆ ): 7.51-7.46 (m, 2H), 6.87 (br s, 2H), 6.64-6.58 (m, 2H), 6.37 (t, J = 5.6 Hz, 1H) , 6.22-6.17 (m, 3H), 5.39 (t, J = 5.6 Hz, 1H), 3.25-3.14 (m, 4H), 2.12 (s, 6H).

Preparation Example 4.3

Preparation of 4-((2-((3,4,5-trimethoxyphenyl)amino)ethyl)amino)benzenesulfonamide

N -(4-sulfamoylphenyl)-2-((3,4,5-trimethoxyphenyl) instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacting with borane dimethyl sulfide complex After transformation using amino)acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 74% yield. ^1H NMR (300 MHz, DMSO- d ₆ ): δ 7.52-7.45 (m, 2H), 6.87 (br s, 2H), 6.65-6.58 (m, 2H), 6.38 (t, J = 6.0 Hz, 1H ), 5.84 (s, 2H), 5.42 (t, J = 6.0 Hz, 1H), 3.65 (s, 6H), 3.49 (s, 3H), 3.26-3.12 (m, 4H).

Preparation Example 4.4

Preparation of 4-((2-(cyclopentylamino)ethyl)amino)benzenesulfonamide

A modification was made to use 2-(cyclopentylamino)- N -(4-sulfamoylphenyl)acetamide instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide, which reacts with the borane dimethyl sulfide complex. According to the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 80% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.49-7.44 (m, 2H), 6.86 (br s, 2H), 6.61-6.56 (m, 2H), 6.25 (t, J = 6.4 Hz, 1H ), 3.12-3.07 (m, 2H), 3.00-2.93 (m, 1H), 2.64 (t, J = 6.4 Hz, 2H), 1.73-1.51 (m, 4H), 1.50-1.37 (m, 2H), 1.30-1.20 (m, 2H).

Preparation Example 4.5

Preparation of 4-((2-(cyclohexylamino)ethyl)amino)benzenesulfonamide

A modification was made to use 2-(cyclohexylamino)- N -(4-sulfamoylphenyl)acetamide instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide, which reacts with the borane dimethyl sulfide complex. According to the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 35% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.49-7.44 (m, 2H), 6.86 (br s, 2H), 6.61-6.56 (m, 2H), 6.25 (t, J = 6.0 Hz, 1H ), 3.09 (q, J = 6.0 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.38-2.29 (m, 1H), 1.82-1.72 (m, 2H), 1.68-1.59 (m, 2H), 1.56-1.47 (m, 1H), 1.24-1.14 (m, 3H), 1.03-0.95 (m, 2H).

Preparation Example 4.6

Preparation of 4-((2-((4-bromo-2-fluorophenyl)amino)ethyl)amino)benzenesulfonamide

2-((4-bromo-2-fluorophenyl)amino)- N -(4-sulfamoyl instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacting with borane dimethyl sulfide complex By transformation using phenyl)acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 74% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.51-7.46 (m, 2H), 7.25 (dd, J = 11.2, 2.4 Hz, 1H), 7.14-7.09 (m, 1H), 6.88 (br s , 2H), 6.68 (t, J = 8.8 Hz, 1H), 6.64-6.58 (m, 2H), 6.44-6.38 (m, 1H), 5.72-5.64 (m, 1H), 3.27-3.20 (m, 4H) ).

Preparation Example 4.7

Preparation of 4-((2-((4-chloro-2-fluorophenyl)amino)ethyl)amino)benzenesulfonamide

2-((4-chloro-2-fluorophenyl)amino)- N -(4-sulfamoylphenyl instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacting with borane dimethyl sulfide complex ) By modification using acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 41% yield.

Preparation Example 4.8

Preparation of 4-((2-((4-(trifluoromethyl)phenyl)amino)ethyl)amino)benzenesulfonamide

N -(4-sulfamoylphenyl)-2-((4-(trifluoromethyl)phenyl)amino instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacting with borane dimethyl sulfide complex ) By modification using acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 67% yield. ^1H NMR (400 MHz, DMSO- d ₆ ): δ 7.51-7.47 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.88 (br s, 2H), 6.66 (d, J = 8.4) Hz, 2H), 6.64-6.60 (m, 2H), 6.44-6.38 (m, 1H), 3.28-3.24 (m, 4H).

Preparation Example 4.9

Preparation of 4-((2-((4-fluorobenzyl)amino)ethyl)amino)benzenesulfonamide

Instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide, which reacts with the borane dimethyl sulfide complex, 2-((4-fluorobenzyl)amino)- N -(4-sulfamoylphenyl)acetamide is used. By making the modifications used and following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 45% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.49-7.44 (m, 2H), 7.38-7.32 (m, 2H), 7.13-7.07 (m, 2H), 6.87 (br s, 2H), 6.61 -6.56 (m, 2H), 6.27 (t, J = 6.0 Hz, 1H), 3.69 (s, 2H), 3.14 (q, J = 6.0 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H) .

Preparation Example 4.10

Preparation of 4-((2-((cyclopropylmethyl)amino)ethyl)amino)benzenesulfonamide

Using 2-((cyclopropylmethyl)amino)- N -(4-sulfamoylphenyl)acetamide instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide, which reacts with borane dimethyl sulfide complex. By modification, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 53% yield. ^1H NMR (400 MHz, DMSO- d ₆ ): δ 7.48-7.43 (m, 2H), 6.86 (br s, 2H), 6.62-6.57 (m, 2H), 6.27 (t, J = 5.6 Hz, 1H), 3.11 (q, J = 6.4 Hz, 2H), 2.69 (t, J = 6.4 Hz, 2H), 2.37 (d, J = 6.4 Hz, 2H), 1.80 (br s, 1H), 0.88-0.78 (m, 1H), 0.39-0.34 (m, 2H), 0.08-0.04 (m, 2H).

Preparation Example 4.11

Preparation of 4-((2-((2-isopropylphenyl)amino)ethyl)amino)benzenesulfonamide

Instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide, which reacts with borane dimethyl sulfide complex, 2-((2-isopropylphenyl)amino)- N -(4-sulfamoylphenyl)acetamide is used. By making the modifications used and following the procedure described in Preparation Example 4, the title compound was obtained as a brown syrup in 86% yield.

Preparation Example 4.12

Preparation of 4-((2-((2-chloro-5-(trifluoromethyl)phenyl)amino)ethyl)amino)benzenesulfonamide

2 -((2-chloro-5-(trifluoromethyl)phenyl)amino) -N- (4 By modification using -sulfamoylphenyl)acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 54% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.51-7.46 (m, 2H), 7.44 (dd, J = 8.4, 0.8 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.89 (br s, 2H), 6.88-6.84 (m, 1H), 6.66-6.61 (m, 2H), 6.48 (t, J = 6.0 Hz, 1H), 5.90 (t, J = 6.0 Hz, 1H), 3.42 -3.35 (m, 2H), 3.30-3.24 (m, 2H).

Preparation Example 4.13

Preparation of 4-((2-((2-fluoro-5-(trifluoromethyl)phenyl)amino)ethyl)amino)benzenesulfonamide

2 -((2-fluoro-5-(trifluoromethyl)phenyl)amino) -N- ( By transformation using 4-sulfamoylphenyl)acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 63% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.51-7.46 (m, 2H), 7.21 (dd, J = 12.0, 8.8 Hz, 1H), 6.94 (dd, J = 8.0, 2.0 Hz, 1H) , 6.92-6.82 (m, 3H), 6.65-6.60 (m, 2H), 6.46-6.41 (m, 1H), 6.02-5.96 (m, 1H), 3.36-3.28 (m, 4H).

Preparation Example 4.14

Preparation of 4-((2-((4-(2-methoxyethoxy)phenyl)amino)ethyl)amino)benzenesulfonamide

2-((4-(2-methoxyethoxy)phenyl)amino) -N- (4-sulfa instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacting with borane dimethyl sulfide complex By modification using moylphenyl)acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a brownish solid in 72% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.51-7.45 (m, 2H), 6.87 (br s, 2H), 6.73-6.68 (m, 2H), 6.63-6.58 (m, 2H), 6.54 -6.48 (m, 2H), 6.37 (t, J = 5.6 Hz, 1H), 5.18 (t, J = 5.6 Hz, 1H), 3.94-3.90 (m, 2H), 3.58-3.55 (m, 2H), 3.26 (s, 3H), 3.24-3.20 (m, 2H), 3.18-3.10 (m, 2H).

Preparation Example 4.15

Preparation of 4-((2-((4-butoxyphenyl)amino)ethyl)amino)benzenesulfonamide

Instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide, which reacts with borane dimethyl sulfide complex, 2-((4-butoxyphenyl)amino)- N -(4-sulfamoylphenyl)acetamide is used. By making the modifications used and following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 47% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.51-7.46 (m, 2H), 6.88 (br s, 2H), 6.71-6.66 (m, 2H), 6.63-6.59 (m, 2H), 6.53 -6.48 (m, 2H), 6.38 (t, J = 5.6 Hz, 1H), 5.16 (t, J = 5.6 Hz, 1H), 3.80 (t, J = 6.4 Hz, 2H), 3.27-3.20 (m, 2H), 3.18-3.10 (m, 2H), 1.65-1.57 (m, 2H), 1.43-1.33 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H).

Preparation Example 4.16

Preparation of 4-((2-(P-tolylamino)ethyl)amino)benzenesulfonamide

A modification using N -(4-sulfamoylphenyl)-2-( p -tolylamino)acetamide instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacts with the borane dimethyl sulfide complex. According to the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 36% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.52-7.49 (m, 2H), 6.98-6.92 (m, 4H), 6.68 (br s, 2H), 6.52-6.48 (m, 2H), 6.55 -6.51 (m, 2H), 6.40 (t, J = 5.2 Hz, 1H), 5.37 (t, J = 5.2 Hz, 1H), 3.30-3.10 (m, 4H), 2.14 (s, 3H).

Preparation Example 4.17

Preparation of 4-((2-((2-fluorophenyl)amino)ethyl)amino)benzenesulfonamide

Instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide, which reacts with borane dimethyl sulfide complex, 2-((2-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide is used. By making the modifications used and following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 95% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.48 (d, J = 8.8 Hz, 2H), 7.02-6.92 (m, 2H), 6.88 (br s, 2H), 6.73 (m, 1H), 6.62 (d, J = 8.8 Hz, 2H), 6.57-6.58 (m, 1H), 6.43 (t, J = 5.2 Hz, 1H), 5.42 (br s, 1H), 3.30-3.22 (m, 4H).

Preparation Example 4.18

Preparation of 4-((2-((2,4-difluorophenyl)amino)ethyl)amino)benzenesulfonamide

2-((2,4-difluorophenyl)amino)- N -(4-sulfamoylphenyl) instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacts with borane dimethyl sulfide complex After transformation using acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 91% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.53 (d, J = 8.7 Hz, 2H), 7.15-7.05 (m, 1H), 6.92 (br s, 2H), 6.90-6.82 (m, 1H) ), 6.81-6.70 (m, 1H), 6.65 (d, J = 8.7 Hz, 2H), 6.47 (br s, 1H), 5.36 (br s, 1H), 3.40-3.20 (m, 4H).

Preparation Example 4.19

Preparation of 4-((2-((4-fluorophenyl)amino)ethyl)amino)benzenesulfonamide

Instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide, which reacts with borane dimethyl sulfide complex, 2-((4-fluorophenyl)amino)- N -(4-sulfamoylphenyl)acetamide is used. By making the modifications used and following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 75% yield. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.51 (d, J = 8.8 Hz, 2H), 7.00-6.81 (m, 4H), 6.63 (d, J = 8.8 Hz, 2H), 6.60-6.50 (m, 2H), 6.45-6.35 (m, 1H), 5.56 (m, 1H), 3.45-3.10 (m, 4H).

Preparation Example 4.20

Preparation of 4-((2-((3-chloro-4-fluorophenyl)amino)ethyl)amino)benzenesulfonamide

2-((3-chloro-4-fluorophenyl)amino)- N -(4-sulfamoylphenyl instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacting with borane dimethyl sulfide complex ) By modification using acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 62% yield. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.49 (d, J = 8.8 Hz, 2H), 7.11-7.06 (m, 1H), 6.88 (br s, 2H), 6.65 (dd, J = 6.0) , 2.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 2H), 6.58-6.48 (m, 1H), 6.38 (t, J = 6.0 Hz, 1H), 6.53 (t, J = 6.0 Hz, 1H) ), 3.30-3.10 (m, 4H).

Preparation Example 4.21

Preparation of 4-((2-((3,5-difluorophenyl)amino)ethyl)amino)benzenesulfonamide

2-((3,5-difluorophenyl)amino)- N -(4-sulfamoylphenyl) instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacts with borane dimethyl sulfide complex By transformation using acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 55% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.49 (d, J = 8.8 Hz, 2H), 6.89 (br s, 2H), 6.61 (d, J = 8.8 Hz, 2H), 6.40-6.30 ( m, 2H), 6.20 (d, J = 11.2 Hz, 2H), 3.30-3.15 (m, 4H).

Preparation Example 4.22

Preparation of 4-((2-((3,4-difluorophenyl)amino)ethyl)amino)benzenesulfonamide

2-((3,4-difluorophenyl)amino)- N -(4-sulfamoylphenyl) instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacts with borane dimethyl sulfide complex After transformation using acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 84% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.48 (d, J = 9.2 Hz, 2H), 7.10-7.05 (m, 1H), 6.88 (br s, 2H), 6.61 (d, J = 9.2 Hz, 2H), 6.68-6.48 (m, 1H), 6.38-6.30 (m, 1H), 3.30-3.10 (m, 4H).

Preparation Example 4.23

Preparation of 4-((2-((2-fluoro-4-methoxyphenyl)amino)ethyl)amino)benzenesulfonamide

2-((2-fluoro-4-methoxyphenyl)amino)- N -(4-sulfamoyl instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacting with borane dimethyl sulfide complex By transformation using phenyl)acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 68% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.48 (d, J = 9.2 Hz, 2H), 6.88 (br s, 2H), 6.73 (dd, J = 10.4, 2.8 Hz, 1H), 6.61 ( d, J = 9.2 Hz, 2H), 6.56 (td, J = 8.8, 2.8 Hz, 1H), 6.52-6.52 (m, 1H), 6.44 (t, J = 5.8 Hz, 1H), 4.79 (t, J = 5.8 Hz, 1H), 3.75 (s, 3H), 3.45-3.15 (m, 4H).

Preparation Example 4.24

Preparation of 4-((2-((4-butoxy-2-fluorophenyl)amino)ethyl)amino)benzenesulfonamide

2-((4-butoxy-2-fluorophenyl)amino)- N -(4-sulfamoyl instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacting with borane dimethyl sulfide complex By transformation using phenyl)acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 80% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.47 (d, J = 8.8 Hz, 2H), 6.87 (br s, 2H), 6.73 (dd, J = 10.8, 2.8 Hz, 1H), 6.61 ( d, J = 8.8 Hz, 2H), 6.57-6.40 (m, 3H), 4.69 (t, J = 5.8 Hz, 1H), 3.92 (t, J = 6.4 Hz, 2H), 3.30-3.20 (m, 4H) ), 1.69-1.61 (m, 2H), 1.45-1.36 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H).

Preparation Example 4.25

Preparation of 4-((2-((4-chloro-3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide

2-((4-chloro-3-fluorophenyl)amino)- N -(4-sulfamoylphenyl instead of 2-bromo- N -(4-sulfamoylphenyl)acetamide reacting with borane dimethyl sulfide complex ) By modification using acetamide, following the procedure described in Preparation Example 4, the title compound was obtained as a white solid in 59% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.48 (d, J = 8.8 Hz, 2H), 7.16 (t, J = 8.8 Hz, 1H), 6.88 (br s, 2H), 6.61 (d, J = 8.8 Hz, 2H), 6.51 (dd, J = 12.8, 2.8 Hz, 1H), 6.45-6.38 (m, 1H), 6.37 (t, J = 8.8 Hz, 1H), 6.17 (t, J = 8.8 Hz, 1H), 3.15-3.30 (m, 4H).

Production example 5

Preparation of 4-(2-methoxyethoxy)aniline

1-(2-Methoxyethoxy)-4-nitrobenzene (1.02 g, 5.17 mmol) and 10% palladium on carbon (150 mg) were mixed in methanol (30 mL). After degassing, a hydrogen gas balloon was added to the mixture. The reaction mixture was stirred at ambient temperature for 2 hours and then filtered through Celite. The filtrate was concentrated and the residue was dried under vacuum to give the title compound as a brown liquid in 70% yield (604 mg), which was used in the next reaction without further purification.

Preparation Example 5.1

Preparation of 2,4-difluoroaniline

Following the procedure described in Preparation Example 5, with the modification of using 2,4-difluoro-1-nitrobenzene instead of 1-(2-methoxyethoxy)-4-nitrobenzene, the title compound was obtained at 92% concentration. It was obtained in good yield. ¹ H NMR (300 MHz, CDCl ₃ ): δ 6.95-6.65 (m, 3H), 3.62 (br s, 2H).

Preparation Example 5.2

Preparation of 2-fluoro-4-methoxyaniline

The title compound was prepared according to the procedure described in Preparation Example 5, with the modification of using 2-fluoro-4-methoxy-1-nitrobenzene instead of 1-(2-methoxyethoxy)-4-nitrobenzene. Obtained in 72% yield. ¹ H NMR (300 MHz, CDCl ₃ ): δ 6.64-6.43 (m, 3H), 3.83 (s, 3H), 3.65 (br s, 2H).

Preparation Example 5.3

Preparation of 4-butoxy-2-fluoroaniline

The title compound was prepared according to the procedure described in Preparation Example 5, with the modification of using 4-butoxy-2-fluoro-1-nitrobenzene instead of 1-(2-methoxyethoxy)-4-nitrobenzene. Obtained in 83% yield. ¹ H NMR (300 MHz, CDCl ₃ ): δ 6.64-6.45 (m, 3H), 3.98 (t, J = 6.5 Hz, 2H), 3.65 (br s, 2H), 1.87-1.78 (m, 2H), 1.56-1.45 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H).

Production example 6

Preparation of 4-((2-((4-cyanophenyl)amino)ethyl)amino)benzenesulfonamide

4-((2-bromoethyl)amino)benzenesulfonamide (200 mg, 0.716 mmol), 4-cyanoaniline (216 mg, 1.83 mmol), and KI (12 mg) were dissolved in an open tube. It was mixed with dichloromethane (2.0 mL) and stirred at 120°C for 10 minutes. The tube was then sealed and the mixture was stirred at 140° C. overnight, cooled to ambient temperature and concentrated. The residue was treated with dichloromethane and filtered. The obtained solid was heated in methanol and filtered. The obtained solid was heated in acetonitrile and filtered. The filtrate was concentrated and the residue was treated with dichloromethane and filtered. The solid was collected and dried under vacuum to give the title compound as a yellowish solid in 31% yield (70.4 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.51-7.47 (m, 2H), 7.45-7.41 (m, 2H), 6.88 (br s, 2H), 6.75-6.70 (m, 1H), 6.66 -6.60 (m, 4H), 6.42-6.38 (m, 1H), 3.29-3.23 (m, 4H).

Preparation Example 6.1

Preparation of 4-((2-((4-acetylphenyl)amino)ethyl)amino)benzenesulfonamide

Following the procedure described in Preparation Example 6, with the modification of using 4-acetylaniline instead of 4-cyanoaniline, which reacts with 4-((2-bromoethyl)amino)benzenesulfonamide, the title compound was produced as a yellow solid. It was obtained in 25% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.73-7.67 (m, 2H), 7.52-7.47 (m, 2H), 6.88 (br s, 2H), 6.66-6.60 (m, 4H), 6.44 -6.39 (m, 1H), 3.30-3.25 (m, 4H), 2.37 (s, 3H).

Production example 7

Preparation of 4-butoxy-2-fluoro-1-nitrobenzene

Butanol (1.56 mL, 17.09 mmol) was added dropwise to a suspension of potassium t -butoxide (3.47 g, 30.96 mmol) in dichloromethane (30 mL) at 0°C. The resulting mixture was stirred for 30 minutes, followed by dropwise addition of 2,4-difluoro-1-nitrobenzene (1.7 mL, 15.48 mmol) at 0°C. The mixture was stirred at ambient temperature for 2 hours and the solvent was removed in vacuo. The residue was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography eluting with hexane:ethyl acetate (9:1) to give the title compound in 66% yield (2.2 g). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.91 (dd, J = 9.2, 3.2 Hz, 1H), 7.80 (dd, J = 10.4, 2.4 Hz, 1H), 6.68 (td, J = 8.8, 2.4 Hz) , 1H), 4.08 (t, J = 6.4 Hz, 2H). 1.90-1.77 (m, 2H), 1.60-1.45 (m, 2H), 0.99 (t, J = 7.5 Hz, 3H).

Example

Example 1

Synthesis of 4-(3-(3-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

To a solution of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide (80 mg, 0.258 mmol) in tetrahydrofuran (10 mL) Phosgene (38 mg, 0.129 mmol) solution was added. The resulting mixture was stirred at ambient temperature for 1 hour and filtered. The filtrate was concentrated and the residue was purified by column chromatography eluting with dichloromethane:methanol (100:1) to give the title compound as a white solid in 19% yield. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.84-7.80 (m, 4H), 7.70-7.60 (m, 1H), 7.43 (m, 1H), 7.27 (br s, 2H), 6.97-6.89 (m, 1H), 4.04-4.00 (m, 4H).

Example 2

Synthesis of 4-(3-(3,5-dimethylphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((3,5-dimethylphenyl)amino)ethyl)amino )Transformation using benzenesulfonamide gave the title compound as an off-white solid in 34% yield following the procedure described in Example 1. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.79-7.75 (m, 4H), 7.24 (m, 2H), 7.21 (br s, 2H), 6.73-6.70 (m, 1H), 4.02-3.88 (m, 4H), 2.25 (s, 6H).

Example 3

Synthesis of 4-(2-(oxo-3-(3,4,5-trimethoxyphenyl)imidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((3,4,5-trimethoxyphenyl)amino Transformation using )ethyl)amino)benzenesulfonamide gave the title compound as an off-white solid in 50% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.80-7.76 (m, 4H), 7.23 (br s, 2H), 6.95 (s, 2H), 4.01-3.97 (m, 4H), 3.77 (s) , 6H), 3.62 (s, 3H).

Example 4

Synthesis of 4-(3-cyclopentyl-2-oxoimidazolidin-1-yl)benzenesulfonamide

Use 4-((2-(cyclopentylamino)ethyl)amino)benzenesulfonamide instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene. With the following modifications, the title compound was obtained in 50% yield as a white solid according to the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.74-7.68 (m, 4H), 7.16 (br s, 2H), 4.22-4.17 (m, 1H), 3.83-3.77 (m, 2H), 3.48 -3.42 (m, 2H), 1.80-1.48 (m, 8H).

Example 5

Synthesis of 4-(3-cyclohexyl-2-oxoimidazolidin-1-yl)benzenesulfonamide

Use 4-((2-(cyclohexylamino)ethyl)amino)benzenesulfonamide instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene. With the following modifications, the title compound was obtained as a white solid in 35% yield according to the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.73-7.66 (m, 4H), 7.16 (br s, 2H), 3.82-3.76 (m, 2H), 3.60 (tt, J = 11.6, 3.6 Hz , 1H), 3.47-3.41 (m, 2H), 1.78-1.71 (m, 2H), 1.67-1.55 (m, 3H), 1.46-1.36 (m, 2H), 1.35-1.23 (m, 2H), 1.13 -1.00 (m, 1H).

Example 6

Synthesis of 4-(3-(4-bromo-2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((4-bromo-2-fluorophenyl)amino Transformation using )ethyl)amino)benzenesulfonamide gave the title compound as an off-white solid in 77% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.80-7.73 (m, 4H), 7.66 (dd, J = 6.8, 2.4 Hz, 1H), 7.53 (t, J = 8.8 Hz, 1H), 7.48 -7.44 (m, 1H), 7.23 (br s, 2H), 4.07-4.00 (m, 2H), 3.97-3.91 (m, 2H).

Example 7

Synthesis of 4-(3-(4-chloro-2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((4-chloro-2-fluorophenyl)amino) A transformation using ethyl)amino)benzenesulfonamide gave the title compound as an off-white solid in 65% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.80-7.74 (m, 4H), 7.61-7.53 (m, 2H), 7.37-7.33 (m, 1H), 7.23 (br s, 2H), 4.07 -4.01 (m, 2H), 3.97-3.91 (m, 2H).

Example 8

Synthesis of 4-(2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((4-(trifluoromethyl)phenyl)amino) Transformation using ethyl)amino)benzenesulfonamide gave the title compound as a white solid in 65% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.84 (d, J = 8.8 Hz, 2H), 7.81-7.79 (m, 4H), 7.72 (d, J = 8.8 Hz, 2H), 7.25 (br s, 2H), 4.05-4.01 (m, 4H).

Example 9

Synthesis of 4-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((4-fluorobenzyl)amino)ethyl)amino) Transformation using benzenesulfonamide gave the title compound as a white solid in 40% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.76-7.70 (m, 4H), 7.37-7.31 (m, 2H), 7.20-7.13 (m, 4H), 4.38 (s, 2H), 3.86- 3.80 (m, 2H), 3.40-3.34 (m, 2H).

Example 10

Synthesis of 4-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((cyclopropylmethyl)amino)ethyl)amino)benzenesulfone Transformation using amides gave the title compound as a white solid in 51% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.74-7.68 (m, 4H), 7.17 (br s, 2H), 3.86-3.80 (m, 2H), 3.60-3.54 (m, 2H), 3.05 (d, J = 7.2 Hz, 2H), 0.96-0.88 (m, 1H), 0.49-0.43 (m, 2H), 0.23-0.17 (m, 2H).

Example 11

Synthesis of 4-(3-(2-isopropylphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((2-isopropylphenyl)amino)ethyl)amino) Transformation using benzenesulfonamide gave the title compound as a white solid in 43% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.78-7.73 (m, 4H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.35-7.28 (m, 2H), 7.26-7.20 ( m, 3H), 4.06-4.00 (m, 2H), 3.83-3.78 (m, 2H), 3.13-3.03 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H).

Example 12

Synthesis of 4-(3-(2-chloro-5-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((2-chloro-5-(trifluorophenyl) Transformation using amino)ethyl)amino)benzenesulfonamide gave the title compound as a white solid in 80% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.00 (d, J = 2.0 Hz, 1H), 7.85-7.70 (m, 6H), 7.23 (br s, 2H), 4.10-4.04 (m, 2H), 3.99-3.93 (m, 2H).

Example 13

Synthesis of 4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-(((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((2-fluoro-5-(trifluoromethyl Transformation using )phenyl)amino)ethyl)amino)benzenesulfonamide gave the title compound as a white solid in 62% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.02 (dd, J = 6.8, 2.0 Hz, 1H), 7.81-7.74 (m, 4H), 7.71-7.66 (m, 1H), 7.59-7.53 ( m, 1H), 7.24 (br s, 2 H), 4.09-3.99 (m, 4H).

Example 14

Synthesis of 4-(3-(4-(2-methoxyethoxy)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

4-(((2-((4-(2-methoxyethoxy)phenyl) instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide which reacts with triphosgene Transformation using amino)ethyl)amino)benzenesulfonamide gave the title compound as a white solid in 45% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.78-7.75 (m, 4H), 7.53-7.47 (m, 2H), 7.21 (br s, 2H), 6.97-6.92 (m, 2H), 4.07 -4.04 (m, 2H), 4.00-3.91 (m, 4H), 3.65-3.61 (m, 2H), 3.29 (s, 3H).

Example 15

Synthesis of 4-(3-(4-butoxyphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((4-butoxyphenyl)amino)ethyl)amino) Transformation using benzenesulfonamide gave the title compound as a white solid in 60% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.78-7.75 (m, 4H), 7.51-7.47 (m, 2H), 7.21 (br s, 2H), 6.95-6.90 (m, 2H), 3.96 -3.90 (m, 6H), 1.70-1.63 (m, 2H), 1.46-1.37 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).

Example 16

Synthesis of 4-(3-(4-cyanophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((4-cyanophenyl)amino)ethyl)amino) Transformation using benzenesulfonamide gave the title compound as a yellowish solid in 85% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.83-7.81 (m, 4H), 7.80-7.78 (m, 4H), 7.25 (br s, 2H), 4.05-4.01 (s, 4H).

Example 17

Synthesis of 4-(3-(4-acetylphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

4-(((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide reacts with triphosgene instead of 4-((2-((4-acetylphenyl)amino)ethyl)amino)benzene Transformation using sulfonamides gave the title compound as a yellow solid in 53% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.99-7.95 (m, 2H), 7.81-7.79 (m, 4H), 7.79-7.75 (m, 2H), 7.25 (br s, 2H), 4.06 -4.01 (m, 4H), 2.53 (s, 3H).

Example 18

Synthesis of 4-(2-oxo-3-( p -tolyl)imidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-( p -tolylamino)ethyl)amino)benzenesulfonamide is used. With the modifications used, the title compound was obtained as a white solid in 46% yield following the procedure described in Example 1. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.82-7.76 (m, 4H), 7.52 (d, J = 8.7 Hz, 2H), 7.24 (br s, 2H), 7.18 (d, J = 8.7) Hz, 2H), 4.10-3.50 (m, 4H), 2.28 (s, 3H). MS (ES-, m/z ): 330.3 (M-1).

Example 19

Synthesis of 4-(3-(2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((2-fluorophenyl)amino)ethyl)amino) Transformation using benzenesulfonamide gave the title compound as a white solid in 53% yield following the procedure described in Example 1. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.86-7.76 (m, 4H), 7.58 (m, 1H), 7.35-7.28 (m, 2H), 7.26-7.16 (m, 2H), 4.10- 4.00 (m, 2H), 3.99-3.90 (m, 2H); MS (ES-, m/z ): 334.3 (M-1).

Example 20

Synthesis of 4-(3-(2,4-difluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((2,4-difluorophenyl)amino)ethyl Transformation using )amino)benzenesulfonamide gave the title compound as a white solid in 19% yield following the procedure described in Example 1. ^1H NMR (300 MHz, DMSO- d ₆ ): δ 7.78 (d, J = 9.6 Hz, 2H), 7.74 (d, J = 9.6 Hz, 2H), 7.58 (td, J = 8.8, 6.4 Hz, 1H ), 7.38 (m, 1H), 7.23 (br s, 2H), 7.15 (m, 1H), 4.05 (m, 2H), 3.95 (m, 2H). MS (ES+, m/z ): 354.2 (M+1).

Example 21

Synthesis of 4-(3-(4-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((4-fluorophenyl)amino)ethyl)amino) Transformation using benzenesulfonamide gave the title compound as a white solid in 10% yield following the procedure described in Example 1. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.79-7.74 (m, 4H), 7.64-7.59 (m, 2H), 7.28-7.17 (m, 4H), 4.10-3.90 (m, 4H). MS (ES-, m/z ): 334.3 (M-1).

Example 22

Synthesis of 4-(3-(3-chloro-4-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((3-chloro-4-fluorophenyl)amino) Transformation using ethyl)amino)benzenesulfonamide gave the title compound as a white solid in 42% yield following the procedure described in Example 1. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.90 (dd, J = 6.4, 2.8 Hz, 1H), 7.82-7.72 (m, 4H), 7.57-7.51 (m, 1H), 7.41 (t, J = 8.8 Hz, 1H), 7.24 (br s, 2H), 4.03-3.86 (m, 4H). MS (ES-, m/z): 368.2 (M-1).

Example 23

Synthesis of 4-(3-(3,5-difluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((3,5-difluorophenyl)amino)ethyl Transformation using )amino)benzenesulfonamide gave the title compound as a white solid in 58% yield following the procedure described in Example 1. ^1H NMR (400 MHz, DMSO- d ₆ ): δ 7.82-7.74 (m, 4H), 7.39 (dd, J = 8.0, 2.4 Hz, 2H), 7.25 (br s, 2H), 7.90 (tt, J = 4.8, 2.4 Hz, 1H), 4.08-3.95 (m, 4H). MS (ES-, m/z ): 352.3 (M-1).

Example 24

Synthesis of 4-(3-(3,4-difluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((3,4-difluorophenyl)amino)ethyl Transformation using )amino)benzenesulfonamide gave the title compound as a white solid in 57% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.86-7.74 (m, 5H), 7.50-7.32 (m, 2H), 7.23 (br s, 2H), 4.05-4.95 (m, 4H). MS (ES-, m/z ): 352.1 (M-1).

Example 25

Synthesis of 4-(3-(2-fluoro-4-methoxyphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((2-fluoro-4-methoxyphenyl)amino Transformation using )ethyl)amino)benzenesulfonamide gave the title compound as a white solid in 27% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.80-7.70 (m, 4H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 7.20 (br s, 2H), 7.03 (dd, J = 8.0, 2.8 Hz, 1H), 7.80 (td, J = 8.8, 2.8 Hz, 1H), 4.01-3.95 (m, 2H), 4.85-3.75 (m, 5H). MS (ES-, m/z ): 364.2 (M-1).

Example 26

Synthesis of 4-(3-(4-butoxy-2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((4-butoxy-2-fluorophenyl)amino Transformation using )ethyl)amino)benzenesulfonamide gave the title compound as a white solid in 51% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.80-7.70 (m, 4H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 7.20 (br s, 2H), 7.01 (dd, J = 8.0, 2.8 Hz, 1H), 6.77 (td, J = 8.8, 2.8 Hz, 1H), 4.05-3.90 (m, 4H), 3.80-3.70 (m, 2H), 1.68-1.62 (m, 2H), 1.40-1.32 (m, 2H), 0.84 (t, J = 7.5 Hz, 3H). MS (ES-, m/z ): 406.3 (M-1).

Example 27

Synthesis of 4-(3-(4-chloro-3-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide

Instead of 4-((2-((3-fluorophenyl)amino)ethyl)amino)benzenesulfonamide, which reacts with triphosgene, 4-((2-((4-chloro-3-fluorophenyl)amino) Transformation using ethyl)amino)benzenesulfonamide gave the title compound as a white solid in 54% yield following the procedure described in Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.82-7.74 (m, 4H), 7.60-7.46 (m, 1H), 7.46-7.36 (m, 1H), 7.24 (br s, 2H), 4.06 -3.94 (m, 4H). MS (ES-, m/z ): 368.1 (M-1).

Example 28

The following compounds were prepared using procedures similar to those described in Example 1.

Biological Example

Example 29

Evaluation of carbonic anhydrase (CA) inhibitory activity

A stopped-flow instrument from Applied Photophysics was used to analyze CA-catalyzed CO ₂ hydration activity. After an initial rate of CA-catalyzed CO ₂ hydration reaction of 10 to 100 s, phenol red (0.2 mM), an indicator operating at an absorbance maximum of 557 nm, was mixed with 20 mM Hepes (pH 7.4) and 20 mM NaBF ₄ . were used together (to maintain a constant ionic strength). CO ₂ concentration ranged from 1.7 to 17 mM for determination of kinetic parameters and inhibition constants. For each inhibitor, at least six traces from the first 5 to 10% of the reaction were used for initial rate measurements. The uncatalyzed rate was measured in the same way and subtracted from the total observed rate. A stock solution (10 mM) of the inhibitor was prepared in distilled-deionized water and then diluted to 0.01 nM with distilled-deionized water. To allow the formation of EI complexes, inhibitor and enzyme solutions were pre-incubated for 15 min at room temperature prior to analysis. Inhibition constants were obtained by nonlinear least squares using PRISM 3, whereas kinetic coefficients for non-inhibited enzymes were derived from Lineweaver-Burk plots and represent the average of at least three different measurements. The table below summarizes the inhibitory activity against CAIX and CAXII of the compounds of the invention. “+” indicates K _i > 100 μM; “++” indicates 100 nM < K _i < 10 nM; “+++” indicates K _i < 10 nM.

Example 30

Cell culture and hypoxia exposure

Acquisition, generation and culture of the luciferase-expressing mouse breast cancer cell lines 4T1, 66cl4 and 67NR and the human breast cancer cell lines MDA-231 and MDA-231 LM2-4 have been described previously (Lou et al, (2008) Dev Dyn 237: 2755-2768; Lou et al, (2011) Cancer Res, 71:3364-3376). For cultivation in hypoxia, cells were maintained at 37°C with 1% O ₂ and 5% CO ₂ balanced with N ₂ in a humidified incubator in a closed anaerobic workstation.

Example 31

stable cell production

shRNAmir vectors (Open Biosystems) targeting mouse CAIX and non-silencing sequences were grown in 90% confluent cells using LipofectAINEPLUSTM (Invitrogen Life Technologies) according to the manufacturer's instructions. was transfected. Due to prior use of puromycin, transfected cells were selected using hygromycin. Stable shCAIX clones were derived by limiting dilution cloning. To (re)introduce CAIX into cells, human CAIX was transfected into 4T1 cells following the same procedure and Zeocin was used for selection.

Example 32

Measurement of extracellular pH

Cells were grown in 60 mm dishes at an appropriate density (1 x 10 ⁴ cells/cm ² for 4T1 cells and transfected derivatives thereof, 2 x 10 ⁴ cells/cm ² for 66Cl4 cells, 67NR cells and transfected derivatives thereof). were plated at 1 x 10 ⁴ cells/cm ² ) and left overnight to allow recovery. Afterwards, a standard volume of 3 ml fresh media per dish was added and cells were cultured under normoxia (air + 5% CO ² ) or hypoxia (1% O ₂ and 5% CO ₂ balanced with nitrogen). Cultured for 72 hours. Care was taken to ensure that cultures grown in normoxia and hypoxia were at similar confluence and contained similar cell numbers at the time of medium collection. The collected spent media was maintained at 37°C and the pH was immediately measured using a digital pH meter. Cell numbers were measured so that the cell numbers for a given cell line could be compared under two environmental conditions. Cells were collected on ice for qRT-PCR and Western blot analysis.

Example 33

cell proliferation essay

Cell growth was measured using the MTT Cell Proliferation Kit (Roche Applied Science) according to the manufacturer's instructions. Briefly, cells were plated in 96-well plates at a density of 5 x 10 ³ cells/cm ² and left overnight for recovery. Thereafter, parallel samples were incubated in normoxia and hypoxia for 48 to 72 hours before performing the assay.

Example 34

3D matrigel infiltration essay

The three-dimensional “on-top” Matrigel culture assay was performed as previously described (Lee et al., (2007) Nat Methods 4:359-365). Briefly, MDA-231, LM2-4 ^, Luc+ cells ( ^1.5 -Plated on well chamber slides. The cells were allowed to adhere for 45 minutes using side-to-side agitation every 10 to 15 minutes to prevent cell aggregation in the center of the well. An additional 100 μl/well medium containing 10% Matrigel was added to the cells and the cultures were grown in hypoxia for 4 days. Images were acquired and cultures were fixed for TUNEL using the “whole culture fixation” methodology outlined in Lee et al, (2007) Nat Methods 4:359-365.

Example 35

Syngeneic orthotopic tumor and spontaneous metastasis

4T1 cells (1 x 10 ⁶ ) or 67NR cells (2 x 10 ⁶ ) were implanted orthotopically into the fourth mammary fat pad of 7-9 week old female BALB/c mice as previously described ( Lou et al, (2011) Cancer Res 71:3364-3376, Lou et al, (2008) Dev Dyn 237:2755-2768). Injections of cell numbers on this scale are standard for the proliferation of these tumors and are much lower than those used in other tumor growth models (Erler, JT. Bennewith, KL, Icolau, M. Nature 440:1222-1226). Primary tumor growth rate was calculated from caliper measurements using the modified ellipsoid formula (L x W ² )/2. Tumor formation and metastatic progression were monitored and quantified using bioluminescent imaging as previously described (Ebos et al., (2009) Cancer Cell 15:232-239, Lou et al., (2008) Dev Dyn 237:2755-2768).

All U.S. patents, U.S. patent application publications, U.S. patent applications, and foreign patents cited herein and/or listed in the application data sheet, including U.S. Provisional Patent Application No. 62/187,636, filed July 1, 2015; Patents, foreign patent applications and non-patent publications are herein incorporated by reference in their entirety.

From the foregoing, it will be appreciated that while specific embodiments of the disclosure are disclosed herein for purposes of explanation, various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, the present invention is not limited, except as defined by the appended claims.

Claims (21)

A compound of formula (Ia), a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof:

here,
R ¹ is unsubstituted C ₃ , C ₅ or C ₆ -cycloalkyl, monocyclic aryl, or pyridinyl;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each hydrogen;
L is a direct bond or methylene (-CH ₂ -); According to paragraph 1,
A compound wherein R ¹ is monocyclic aryl substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy, heterocyclyl, haloalkyl, cyano, and acetyl. According to paragraph 2,
4-(3-(4-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(2,4-difluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(2-oxo-3-(p-tolyl)imidazolidin-1-yl)benzenesulfonamide;
4-(3-(2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(3-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(3,5-dimethylphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(2-oxo-3-(3,4,5-trimethoxyphenyl)imidazolidin-1-yl)benzenesulfonamide;
4-(3-(2-fluoro-4-morpholinophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(4-bromo-2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(4-chloro-2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)benzenesulfonamide;
4-(3-(4-chloro-3-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(2-fluoro-4-methoxyphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(4-(2-methoxyethoxy)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(2-isopropylphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(3,5-difluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(3-chloro-4-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(3,4-difluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(2-chloro-5-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(4-butoxy-2-fluorophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(4-butoxyphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-(4-cyanophenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide; or
A compound that is 4-(3-(4-acetylphenyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide. According to paragraph 1,
4-(3-cyclopentyl-2-oxoimidazolidin-1-yl)benzenesulfonamide;
4-(3-cyclohexyl-2-oxoimidazolidin-1-yl)benzenesulfonamide; or
A compound that is 4-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)benzenesulfonamide. According to paragraph 1,
A compound that is 4-(3-(5-fluoropyridin-2-yl)-2-oxoimidazolidin-1-yl)benzenesulfonamide. A pharmaceutical composition comprising the compound of any one of claims 1 to 5 and a pharmaceutically acceptable excipient,
A pharmaceutical composition for use in a method of inhibiting tumor growth, invasion and/or tumor metastasis in a mammal in need of treatment comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition. A pharmaceutical composition comprising the compound of any one of claims 1 to 5 and a pharmaceutically acceptable excipient,
Used in a method of treating a mammal with cancer comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition, wherein the cancer is astrocytoma/glioblastoma, bladder cancer, breast cancer, colon carcinoma, esophageal adenocarcinoma, gastrointestinal stromal tumor. , stomach cancer, head and neck cancer, hepatocellular carcinoma, lung cancer, melanoma, ovarian cancer, pancreatic ductal adenocarcinoma, renal cell carcinoma, thyroid cancer, or endometrial cancer. In clause 7,
A pharmaceutical composition, wherein treating a mammal with cancer comprises reducing or eliminating metastases. In clause 7,
A pharmaceutical composition, wherein the method further comprises administering an additional chemotherapy agent or other anti-cancer agent. A pharmaceutical composition comprising the compound of any one of claims 1 to 5 and a pharmaceutically acceptable excipient,
A pharmaceutical composition for use in a method of removing cancer stem cells from a population of mammalian cancer stem cells comprising contacting the population of mammalian cancer stem cells with a pharmaceutical composition. A pharmaceutical composition comprising the compound of any one of claims 1 to 5 and a pharmaceutically acceptable excipient,
A pharmaceutical composition for use in a method of inducing cell death in hypoxic cancer cells comprising contacting the hypoxic cancer cells with a pharmaceutical composition. According to clause 6,
A pharmaceutical composition wherein the tumor growth, invasion and/or tumor metastasis is a solid tumor or liquid tumor. delete delete delete delete delete delete delete delete delete